NM_004329.3(BMPR1A):c.383A>G (p.Asn128Ser) AND Juvenile polyposis syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000469945.16

Allele description [Variation Report for NM_004329.3(BMPR1A):c.383A>G (p.Asn128Ser)]

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

Gene:

BMPR1A:bone morphogenetic protein receptor type 1A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.2

Genomic location:

Preferred name:

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

HGVS:

NC_000010.11:g.86899843A>G
NG_009362.1:g.148205A>G
NM_004329.3:c.383A>GMANE SELECT
NP_004320.2:p.Asn128Ser
NP_004320.2:p.Asn128Ser
LRG_298t1:c.383A>G
LRG_298:g.148205A>G
LRG_298p1:p.Asn128Ser
NC_000010.10:g.88659600A>G
NM_004329.2:c.383A>G
p.N128S

Protein change:

N128S

Links:

dbSNP: rs375165807

NCBI 1000 Genomes Browser:

rs375165807

Molecular consequence:

NM_004329.3:c.383A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Juvenile polyposis syndrome (JPS)
Synonyms:: Polyposis juvenile intestinal; Polyposis familial of entire gastrointestinal tract
Identifiers:: MONDO: MONDO:0017380; MedGen: C0345893; Orphanet: 2929; OMIM: 174900

Recent activity

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undecaprenyl-phosphate glucose phosphotransferase [Vibrio antiquarius]
undecaprenyl-phosphate glucose phosphotransferase [Vibrio antiquarius]
gi|493794114|ref|WP_006742212.1|

Protein
Gomphus cf. floccosus voucher G-010 28S ribosomal RNA gene, partial sequence
Gomphus cf. floccosus voucher G-010 28S ribosomal RNA gene, partial sequence
gi|6959762|gb|AF213130.1|

Nucleotide
FCF1P8 FCF1 pseudogene 8 [Homo sapiens]
FCF1P8 FCF1 pseudogene 8 [Homo sapiens]
Gene ID:100422531

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000552883	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25559809, 28492532
SCV004842849	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25559809, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000552883

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 27, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004842849

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 30, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	7	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.

Chubb D, Broderick P, Frampton M, Kinnersley B, Sherborne A, Penegar S, Lloyd A, Ma YP, Dobbins SE, Houlston RS.

J Clin Oncol. 2015 Feb 10;33(5):426-32. doi: 10.1200/JCO.2014.56.5689. Epub 2015 Jan 5.

PubMed [citation]

PMID:: 25559809

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000552883.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004842849.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		7	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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