rs35572415

chr10-86919443-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004329.3(BMPR1A):c.1140C>T(p.Asp380=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.03

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 -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. This position pass quality control queck.
• BS2: High AC in GnomAd at 2287 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.1140C>T	p.Asp380=	synonymous_variant	10/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.1140C>T	p.Asp380=	synonymous_variant	10/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2287 AN: 152132 Hom.: 24 Cov.: 32

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.: 34 AF XY: 0.0152 AC XY: 2064 AN XY: 135696

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.: 32 AF XY: 0.0189 AC XY: 13731 AN XY: 726878

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.: 24 Cov.: 32 AF XY: 0.0146 AC XY: 1086 AN XY: 74430

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.: 14

Bravo AF: 0.0168

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0248

EpiControl AF: 0.0248

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 12, 2016	- -
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	Clinical Genetics, Academic Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 18, 2019	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2016	- -

Juvenile polyposis syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

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

Other links and lift over

dbSNP: rs35572415; hg19: chr10-88679200; COSMIC: COSV64405088;