VCV000186487.26 - ClinVar

NM_004329.3(BMPR1A):c.383A>G (p.Asn128Ser)

Germline

Classification

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(7); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004329.3(BMPR1A):c.383A>G (p.Asn128Ser)

Variation ID: 186487 Accession: VCV000186487.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.2 10: 86899843 (GRCh38) [ NCBI UCSC ] 10: 88659600 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Apr 29, 2017	Sep 29, 2024	Jan 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004329.3:c.383A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004320.2:p.Asn128Ser	missense
NC_000010.11:g.86899843A>G
NC_000010.10:g.88659600A>G
NG_009362.1:g.148205A>G
LRG_298:g.148205A>G
LRG_298t1:c.383A>G	LRG_298p1:p.Asn128Ser

... more HGVS ... less HGVS

Protein change

N128S

Other names

Canonical SPDI

NC_000010.11:86899842:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA194960 dbSNP: rs375165807 VarSome

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
Gene	OMIM	HI score Help 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.
BMPR1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2329	2425

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.
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Dec 15, 2022	RCV000166089.16
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 1, 2023	RCV000479183.7
Juvenile polyposis syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 27, 2024	RCV000469945.16
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV001818388.5

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.
Uncertain significance (Jul 31, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002070335.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the BMPR1A gene demonstrated a sequence change, c.383A>G, in exon 6 that results in an amino acid change, p.Asn128Ser. This sequence … (more) DNA sequence analysis of the BMPR1A gene demonstrated a sequence change, c.383A>G, in exon 6 that results in an amino acid change, p.Asn128Ser. This sequence change does not appear to have been previously described in patients with BMPR1A-related disorders. This sequence change has been described in the gnomAD database with a low population frequency of 0.003% (dbSNP rs375165807). The p.Asn128Ser change affects a moderately conserved amino acid residue located in the extracellular domain of the BMPR1A protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn128Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn128Ser change remains unknown at this time. (less)
Benign (Aug 18, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000216854.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 25559809 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Nov 22, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002528599.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The BMPR1A c.383A>G (p.N128S) missense variant has been reported in 1 individual with colorectal cancer (PMID: 25559809). This variant was observed in 5/113742 chromosomes in … (more) The BMPR1A c.383A>G (p.N128S) missense variant has been reported in 1 individual with colorectal cancer (PMID: 25559809). This variant was observed in 5/113742 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (PMID: 32461654). The variant has been reported in ClinVar (Variation ID 186487). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (1) PubMed: 25559809
Uncertain significance (Dec 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000682889.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Comment: This missense variant replaces asparagine with serine at codon 128 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces asparagine with serine at codon 128 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has been identified in 7/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Juvenile polyposis syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000552883.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 28492532‚ 25559809 Comment: This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 128 of the BMPR1A protein (p.Asn128Ser). … (more) This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 128 of the BMPR1A protein (p.Asn128Ser). This variant is present in population databases (rs375165807, gnomAD 0.004%). This missense change has been observed in individual(s) with tubular adenoma and hyperplastic polyps (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 186487). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Oct 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile polyposis syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004842849.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (1) PubMed: 25559809 Comment: This missense variant replaces asparagine with serine at codon 128 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces asparagine with serine at codon 128 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 25559809). This variant has also been identified in 7/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 7
Uncertain significance (Nov 01, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000569008.6 First in ClinVar: Apr 29, 2017 Last updated: Sep 29, 2024	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with personal and family history of colorectal cancer/polyps … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with personal and family history of colorectal cancer/polyps (PMID: 25559809); This variant is associated with the following publications: (PMID: 30787465, 22799562, 23433720, 10881198, 25559809) (less)
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004027584.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023

Comment:

DNA sequence analysis of the BMPR1A gene demonstrated a sequence change, c.383A>G, in exon 6 that results in an amino acid change, p.Asn128Ser. This sequence change does not appear to have been previously described in patients with BMPR1A-related disorders. This sequence change has been described in the gnomAD database with a low population frequency of 0.003% (dbSNP rs375165807). The p.Asn128Ser change affects a moderately conserved amino acid residue located in the extracellular domain of the BMPR1A protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn128Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn128Ser change remains unknown at this time.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This missense variant replaces asparagine with serine at codon 128 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has been identified in 7/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 128 of the BMPR1A protein (p.Asn128Ser). This variant is present in population databases (rs375165807, gnomAD 0.004%). This missense change has been observed in individual(s) with tubular adenoma and hyperplastic polyps (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 186487). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This missense variant replaces asparagine with serine at codon 128 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 25559809). This variant has also been identified in 7/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with personal and family history of colorectal cancer/polyps (PMID: 25559809); This variant is associated with the following publications: (PMID: 30787465, 22799562, 23433720, 10881198, 25559809)

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.

Comment:

This missense variant replaces asparagine with serine at codon 128 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 25559809). This variant has also been identified in 7/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.	Chubb D	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 25559809

Text-mined citations for rs375165807 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_004329.3(BMPR1A):c.383A>G (p.Asn128Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs375165807 ...