rs56108371

chr10-86917235-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004329.3(BMPR1A):c.777G>A(p.Ala259=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (14 hom.)
• Consequence: BMPR1A NM_004329.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.625

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 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.777G>A	p.Ala259=	synonymous_variant	9/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.777G>A	p.Ala259=	synonymous_variant	9/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152124 Hom.: 3 Cov.: 32

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.: 0 AF XY: 0.000701 AC XY: 95 AN XY: 135456

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.: 14 Cov.: 32 AF XY: 0.000828 AC XY: 602 AN XY: 727102

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.: 3 Cov.: 32 AF XY: 0.00198 AC XY: 147 AN XY: 74428

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.: 0

Bravo AF: 0.00201

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	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	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 17, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 27, 2018	- -
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. -

Juvenile polyposis syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BMPR1A: BP4, BP7, BS1, BS2 -
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. -

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

Other links and lift over

dbSNP: rs56108371; hg19: chr10-88676992;