ClinVar Genomic variation as it relates to human health
NM_005359.6(SMAD4):c.1140-10T>C
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(1); Benign(12); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005359.6(SMAD4):c.1140-10T>C
Variation ID: 139219 Accession: VCV000139219.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 51067009 (GRCh38) [ NCBI UCSC ] 18: 48593379 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 24, 2015 May 12, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005359.6:c.1140-10T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000018.10:g.51067009T>C NC_000018.9:g.48593379T>C NG_013013.2:g.103970T>C LRG_318:g.103970T>C LRG_318t1:c.1140-10T>C - Protein change
- Other names
- -
- Canonical SPDI
- NC_000018.10:51067008:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00240 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00047
Exome Aggregation Consortium (ExAC) 0.00055
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
Trans-Omics for Precision Medicine (TOPMed) 0.00206
The Genome Aggregation Database (gnomAD) 0.00221
1000 Genomes Project 0.00240
1000 Genomes Project 30x 0.00281
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SMAD4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2075 | 2117 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2021 | RCV000128173.19 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 1, 2023 | RCV000586605.15 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 23, 2021 | RCV000579485.4 | |
Benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV001080462.7 | |
Benign (1) |
criteria provided, single submitter
|
Jan 13, 2018 | RCV001127535.5 | |
Benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV001127536.5 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001507129.7 | |
Likely benign (1) |
criteria provided, single submitter
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Aug 23, 2021 | RCV002492489.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 21, 2015 | RCV002453458.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Benign
(Mar 04, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000171765.11
First in ClinVar: Jun 23, 2014 Last updated: Feb 24, 2015 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Mar 14, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806690.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000252797.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Benign
(May 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698563.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.1140-10T>C variant affects a non-conserved intronic nucleotide. Mutation taster predicts benign outcome for this variant. 5/5 programs in Alamut predict that this … (more)
Variant summary: The c.1140-10T>C variant affects a non-conserved intronic nucleotide. Mutation taster predicts benign outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is found in 66/120780 control chromosomes at a frequency of 0.0005464, which greatly exceeds the maximal expected frequency of a pathogenic allele (0.000002) in this gene, suggesting this variant is benign. In addition, independent clinical diagnostic laboratories classify the variant as Benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Based on the high prevalence of the variant in the general population, it was classified as Benign. (less)
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Benign
(Apr 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159062.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001286856.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001286857.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Myhre syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001286858.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Benign
(Aug 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067442.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Jan 23, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002538292.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(May 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002613187.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.1140-10T>C intronic variant results from a T to C substitution 10 nucleotides upstream from coding exon 9 in the SMAD4 gene. This variant was … (more)
The c.1140-10T>C intronic variant results from a T to C substitution 10 nucleotides upstream from coding exon 9 in the SMAD4 gene. This variant was previously reported in the SNPDatabase as rs186332162. Based on data from the 1000 Genomes Project, the C allele has an overall frequency of approximately 0.1% (2/2098) total alleles studied. The highest observed frequency was 0.94% (1/106) African-American SW alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.09% (12/13006) total alleles studied, having been observed in 0.25% (11/4406) African American alleles and 0.01% (1/8600) European American alleles. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this acceptor/donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
Number of individuals with the variant: 1
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Benign
(Mar 09, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000686515.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
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Benign
(Mar 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889839.3
First in ClinVar: Mar 17, 2018 Last updated: Dec 31, 2022 |
|
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Likely benign
(Aug 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Myhre syndrome
Juvenile polyposis syndrome Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Carcinoma of pancreas
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002801979.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Likely benign
(Oct 01, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004143106.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
SMAD4: BS1
Number of individuals with the variant: 3
|
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957411.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969602.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs186332162 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.