rs786203157

Positions:

• chr10-86876019-A-C
• chr10-86876019-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001406588.1(BMPR1A):​c.-79A>C variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMPR1A NM_001406588.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 10-86876019-A-C is Pathogenic according to our data. Variant chr10-86876019-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1A	NM_004329.3	c.1A>C	p.Met1?	initiator_codon_variant	3/13	ENST00000372037.8	NP_004320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8	c.1A>C	p.Met1?	initiator_codon_variant	3/13	1	NM_004329.3	ENSP00000361107.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2019	​The p.M1L pathogenic mutation (also known as c.1A>C) is located in coding exon 1 of the BMPR1A gene and results from an A to C substitution at nucleotide position 1. This changes the amino acid from a methionine to a leucine at the initiation codon. This mutation has been described in a patient with sporadic juvenile polyposis (Calva-Cerqueira D. et al. Clin Genet. 2009 Jan;75(1):79-85). Functional studies for this variant are conflicting with aberrant subcellular localization, intact bone morphogenetic protein (BMP) signaling, and reduced BMPR1A protein expression being demonstrated; however, BMPR1A protein may have failed to be detected due to a loss of the N-terminal portion of the protein with use of an alternate downstream start codon (Howe JR et al. J. Surg. Res., 2013 Oct;184:739-45). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 29, 2020	This variant results in the loss of the translation start codon of the BMPR1A gene. The next in-frame methionine occurs at codon 29 that if used would delete the N-terminal signal peptide sequence (a.a. 1-23). The signal peptide motif is required for membrane-localization of the protein (PMID: 23433720). One study has shown that cells transfected with a construct containing this variant lacked the full-length BMPR1A protein product (PMID: 23433720). A protein product mislocalized to the cytoplasm was detected, but this study was inconclusive regarding the ability of the cytoplasmic protein to transduce BMP signaling. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD) and has been reported in an individual affected with juvenile polyposis (PMID: 18823382). Different variants that also result in the loss of p.Met1 have reported as disease-causing in ClinVar (variation ID: 186704, 224521, 653050, 824482, 843741), suggesting that this codon is important for protein expression and/or function. Loss of BMPR1A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Juvenile polyposis syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 25, 2023

This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.033
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.39	T
PROVEAN	Benign	-0.21	N;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.96
MutPred		0.97		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs786203157; hg19: chr10-88635776;