rs876660939

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The ENST00000372037.8(BMPR1A):​c.902C>A​(p.Ser301Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S301T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

BMPR1A
ENST00000372037.8 missense

Scores

11
5
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
BMPR1A (HGNC:1076): (bone morphogenetic protein receptor type 1A) The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF-beta superfamily. TGF-betas and activins transduce their signals through the formation of heteromeric complexes with 2 different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BMPR1A. . Gene score misZ 1.9176 (greater than the threshold 3.09). Trascript score misZ 3.8989 (greater than threshold 3.09). GenCC has associacion of gene with polyposis syndrome, hereditary mixed, 2, generalized juvenile polyposis/juvenile polyposis coli, hereditary mixed polyposis syndrome, pulmonary arterial hypertension, juvenile polyposis syndrome.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BMPR1ANM_004329.3 linkuse as main transcriptc.902C>A p.Ser301Tyr missense_variant 10/13 ENST00000372037.8 NP_004320.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BMPR1AENST00000372037.8 linkuse as main transcriptc.902C>A p.Ser301Tyr missense_variant 10/131 NM_004329.3 ENSP00000361107 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2024The p.S301Y variant (also known as c.902C>A), located in coding exon 8 of the BMPR1A gene, results from a C to A substitution at nucleotide position 902. The serine at codon 301 is replaced by tyrosine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 06, 2023This missense variant replaces serine with tyrosine at codon 301 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 not been identified 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. -
Juvenile polyposis syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMay 14, 2024This missense variant replaces serine with tyrosine at codon 301 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 not been identified 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. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 20, 2023This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 301 of the BMPR1A protein (p.Ser301Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 234223). 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%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
1.0
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Uncertain
0.67
D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Benign
1.9
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-4.2
D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.47
MutPred
0.43
Loss of catalytic residue at S301 (P = 0.1079);
MVP
0.90
MPC
3.2
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.93
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs876660939; hg19: chr10-88678962; API