10-86876021-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_004329.3(BMPR1A):c.3G>T(p.Met1?) variant causes a start lost 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMPR1A NM_004329.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.40

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.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_004329.3 (BMPR1A) was described as [Likely_pathogenic] in ClinVar as 224521
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-86876021-G-T is Pathogenic according to our data. Variant chr10-86876021-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 843741.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.3G>T	p.Met1?	start_lost	3/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.3G>T	p.Met1?	start_lost	3/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Juvenile polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

This sequence change affects the initiator methionine of the BMPR1A mRNA. The next in-frame methionine is located at codon 29. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of juvenile polyposis syndrome (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 843741). While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the disruption of the signal peptide (residues 1-23), which is important for BMPR1A-mediated cellular localization (PMID: 23433720). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.052
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.29	N;.
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.93
MutPred		0.95		Gain of catalytic residue at M1 (P = 0.0204);Gain of catalytic residue at M1 (P = 0.0204);
MVP		0.96
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.68

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

Other links and lift over

dbSNP: rs869312758; hg19: chr10-88635778; COSMIC: COSV64408822;