rs869312758

chr10-86876021-G-Achr10-86876021-G-Cchr10-86876021-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>A(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-A is Pathogenic according to our data. Variant chr10-86876021-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 824482.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-86876021-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.3G>A	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>A	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

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2019

The p.M1? variant (also known as c.3G>A) is located in coding exon 1 of the BMPR1A gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. There is an in-frame methionine 29 amino acids downstream from this initiation site which may result in an N-terminal truncation; however, direct evidence is unavailable. Based on an internal structural analysis, this N-terminal truncation is anticipated to result in disruption of the BMPR1A signaling motif. This variant was identified in a proband meeting clinical diagnostic criteria for juvenile polyposis syndrome (Ambry internal data). Other variants that affect the initiation codon of BMPR1A, c.1A>C and c.1A>G, have been identified in individuals with juvenile polyposis (Calva-Cerqueira D. et al. Clin. Genet. 2009 Jan;75:79-85; Howe JR et al. J. Surg. Res. 2013 Oct;184:739-45; Ambry internal data). 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. -

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	0.97
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.052
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.69	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;