rs56108371

Positions:

chr10-86917235-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004329.3(BMPR1A):c.777G>A(p.Ala259Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,613,860 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 14 hom. )

Consequence

BMPR1A
NM_004329.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.625

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]

BMPR1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 10-86917235-G-A is Benign according to our data. Variant chr10-86917235-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86917235-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.625 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00198 (301/152242) while in subpopulation EAS AF= 0.00984 (51/5182). AF 95% confidence interval is 0.00769. There are 3 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1A	NM_004329.3 link	c.777G>A	p.Ala259Ala	synonymous_variant	9/13	ENST00000372037.8	NP_004320.2	P36894

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8 link	c.777G>A	p.Ala259Ala	synonymous_variant	9/13	1	NM_004329.3	ENSP00000361107.2		P36894

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00522

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0100

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000851

AC:

213

AN:

250416

Hom.:

AF XY:

0.000701

AC XY:

AN XY:

135456

show subpopulations

Gnomad AFR exome

AF:

0.00416

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00447

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.000650

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000846

AC:

1237

AN:

1461618

Hom.:

Cov.:

AF XY:

0.000828

AC XY:

602

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00514

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0197

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.000656

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.000812

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152242

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

147

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00522

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00984

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000748

Hom.:

Bravo

AF:

0.00201

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2014	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 27, 2018	- -

Juvenile polyposis syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 05, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 01, 2016	Variant summary: The BMPR1A c.777G>A (p.Ala259Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant while 4/5 splice tools predict the variant not to have an impact on normal splicing. This variant was found in 113/120202 control chromosomes at a frequency of 0.0009401, which is approximately 470 times the estimated maximal expected allele frequency of a pathogenic BMPR1A variant (0.000002), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign/Likely Benign. Taken together, this variant is classified as Benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	BMPR1A: BP4, BP7, BS1, BS2 -

Generalized juvenile polyposis/juvenile polyposis coli

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 29, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.8

DANN

Benign

0.73

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over