rs1329735599

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_004329.3(BMPR1A):​c.1471G>A​(p.Glu491Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BMPR1A
NM_004329.3 missense, splice_region

Scores

8
5
5
Splicing: ADA: 0.9533
1
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 8.19
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. GenCC has associacion of the gene with polyposis syndrome, hereditary mixed, 2, generalized juvenile polyposis/juvenile polyposis coli, hereditary mixed polyposis syndrome, pulmonary arterial hypertension, juvenile polyposis syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BMPR1ANM_004329.3 linkc.1471G>A p.Glu491Lys missense_variant, splice_region_variant 12/13 ENST00000372037.8 NP_004320.2 P36894

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BMPR1AENST00000372037.8 linkc.1471G>A p.Glu491Lys missense_variant, splice_region_variant 12/131 NM_004329.3 ENSP00000361107.2 P36894

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251494
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 07, 2019The p.E491K variant (also known as c.1471G>A), located in coding exon 10 of the BMPR1A gene, results from a G to A substitution at nucleotide position 1471. The glutamic acid at codon 491 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 HealthMay 16, 2019- -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Dec 13, 2021- -
Polyposis syndrome, hereditary mixed, 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsAug 18, 2023- -
Juvenile polyposis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 03, 2023This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 491 of the BMPR1A protein (p.Glu491Lys). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 489689). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
D
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Benign
0.017
T
MetaRNN
Pathogenic
0.80
D
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
0.90
L
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.2
D
REVEL
Uncertain
0.52
Sift
Uncertain
0.0090
D
Sift4G
Benign
0.084
T
Polyphen
1.0
D
Vest4
0.75
MutPred
0.61
Gain of methylation at E491 (P = 0.0035);
MVP
0.79
MPC
1.6
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.76
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.95
dbscSNV1_RF
Pathogenic
0.82
SpliceAI score (max)
0.0
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: rs1329735599; hg19: chr10-88683261; API