4-95104435-G-A

Position:

chr4-95104435-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_001203.3(BMPR1B):c.11G>A(p.Arg4Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000391 in 1,612,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

BMPR1B
NM_001203.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 5.57

Variant links:

Genes affected

BMPR1B (HGNC:1077): (bone morphogenetic protein receptor type 1B) This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are BMPs, which are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of 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. Mutations in this gene have been associated with primary pulmonary hypertension. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

BMPR1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.104444355).

BP6

Variant 4-95104435-G-A is Benign according to our data. Variant chr4-95104435-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 906582.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr4-95104435-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000277 (42/151874) while in subpopulation NFE AF= 0.000485 (33/67972). AF 95% confidence interval is 0.000355. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1B	NM_001203.3 linkuse as main transcript	c.11G>A	p.Arg4Gln	missense_variant	4/13	ENST00000515059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1B	ENST00000515059.6 linkuse as main transcript	c.11G>A	p.Arg4Gln	missense_variant	4/13	1	NM_001203.3	P4	O00238-1

Frequencies

GnomAD3 genomes

AF:

0.000277

AC:

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000375

AC:

AN:

250824

Hom.:

AF XY:

0.000472

AC XY:

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000652

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.000402

AC:

588

AN:

1461088

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

304

AN XY:

726828

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000468

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000277

AC:

AN:

151874

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

AN XY:

74132

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000263

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000574

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.00115

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acromesomelic dysplasia 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 06, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

BMPR1B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2024

The BMPR1B c.11G>A variant is predicted to result in the amino acid substitution p.Arg4Gln. This variant has been reported as uncertain in an individual with primary ovarian insufficiency (reported as p.Arg34Gln in Table S7, Heddar. et al 2022. PubMed ID: 36099812). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has been reported as benign/likely benign/uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/906582/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2019

Reported in an abstract in patients with primary ovarian insufficiency; no other details aee available to GeneDx (Rossetti et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Idiopathic pulmonary arterial hypertension

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Aug 27, 2021

- -

Brachydactyly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Type A2 brachydactyly;C4225404:Acromesomelic dysplasia 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;T;.;.;T;T

Eigen

Benign

-0.055

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

.;D;.;D;D;.;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.10

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.3

L;.;L;.;.;L;L

MutationTaster

Benign

0.98

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.21

N;N;N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.16

T;T;T;T;T;T;T

Sift4G

Benign

0.17

T;D;T;T;D;T;T

Polyphen

0.0070

B;.;B;.;.;B;B

Vest4

0.35

MVP

0.95

MPC

0.26

ClinPred

0.027

GERP RS

5.5

Varity_R

0.14

gMVP

0.58

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

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