rs35572415

Positions:

chr10-86919443-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004329.3(BMPR1A):c.1140C>T(p.Asp380Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,362 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 32)

Exomes 𝑓: 0.019 ( 323 hom. )

Consequence

BMPR1A
NM_004329.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 1.03

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:

BMPR1A (HGNC:):

BMPR1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 10-86919443-C-T is Benign according to our data. Variant chr10-86919443-C-T is described in ClinVar as [Benign]. Clinvar id is 132691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86919443-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.015 (2285/152250) while in subpopulation AMR AF= 0.0242 (371/15302). AF 95% confidence interval is 0.0222. There are 24 homozygotes in gnomad4. There are 1086 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2285 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1A	NM_004329.3 linkuse as main transcript	c.1140C>T	p.Asp380Asp	synonymous_variant	10/13	ENST00000372037.8	NP_004320.2	P36894

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8 linkuse as main transcript	c.1140C>T	p.Asp380Asp	synonymous_variant	10/13	1	NM_004329.3	ENSP00000361107.2		P36894

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2287

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.0146

AC:

3665

AN:

251006

Hom.:

AF XY:

0.0152

AC XY:

2064

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.00369

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00823

Gnomad FIN exome

AF:

0.00614

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0192

AC:

27985

AN:

1461112

Hom.:

323

Cov.:

AF XY:

0.0189

AC XY:

13731

AN XY:

726878

show subpopulations

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.0158

Gnomad4 ASJ exome

AF:

0.0136

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00779

Gnomad4 FIN exome

AF:

0.00642

Gnomad4 NFE exome

AF:

0.0221

Gnomad4 OTH exome

AF:

0.0178

GnomAD4 genome

AF:

0.0150

AC:

2285

AN:

152250

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1086

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00407

Gnomad4 AMR

AF:

0.0242

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.00584

Gnomad4 NFE

AF:

0.0224

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0177

Hom.:

Bravo

AF:

0.0168

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0248

EpiControl

AF:

0.0248

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 12, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BMPR1A p.Asp380= variant was identified in 1 of 96 proband chromosomes (frequency: 0.01) from one individual with Hereditary hemorrhagic telangiectasia; however, the variant is identified as a polymorphism (Lesca 2006). The variant was also identified in the following databases: dbSNP (ID: rs35572415) as "With Likely benign allele", ClinVar (5x benign, 1x likely benign), Clinvitae, and LOVD 3.0 (4x). The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 3968 of 276746 chromosomes (34 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 92 of 24020 chromosomes (freq: 0.004), Other in 129 of 6460 chromosomes (freq: 0.02), Latino in 477 of 34416 chromosomes (freq: 0.01), European in 2719 of 126260 chromosomes (freq: 0.02), Ashkenazi Jewish in 149 of 10150 chromosomes (freq: 0.01), Finnish in 154 of 25792 chromosomes (freq: 0.006), and South Asian in 248 of 30782 chromosomes (freq: 0.008). The variant was not observed in the East Asian population. A study by Pyatt 2006 investigating Juvenile polyposis syndrome listed this variant as a polymorphism. The p.Asp380= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 14, 2020	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 18, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2014	This alteration is classified as 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, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -

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	Myriad Genetics, Inc.	Aug 06, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Generalized juvenile polyposis/juvenile polyposis coli

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.7

DANN

Benign

0.52

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