rs34970181

chr4-95148783-G-Achr4-95148783-G-Cchr4-95148783-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001203.3(BMPR1B):c.1112G>A(p.Arg371Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,613,874 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R371L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: BMPR1B NM_001203.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 8.00

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13577956).
• BP6: Variant 4-95148783-G-A is Benign according to our data. Variant chr4-95148783-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 441001.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000861 (131/152138) while in subpopulation SAS AF= 0.00187 (9/4816). AF 95% confidence interval is 0.000975. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1B	NM_001203.3	c.1112G>A	p.Arg371Gln	missense_variant	11/13	ENST00000515059.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1B	ENST00000515059.6	c.1112G>A	p.Arg371Gln	missense_variant	11/13	1	NM_001203.3	P4

Frequencies

GnomAD3 genomes AF: 0.000862 AC: 131 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000994 AC: 250 AN: 251396 Hom.: 1 AF XY: 0.000935 AC XY: 127 AN XY: 135872

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000941 AC: 1375 AN: 1461736 Hom.: 1 Cov.: 31 AF XY: 0.000898 AC XY: 653 AN XY: 727166

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000986

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000861 AC: 131 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000928 AC XY: 69 AN XY: 74386

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000936 Hom.: 0

Bravo AF: 0.000808

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.000873

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

BMPR1B-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2023

The BMPR1B c.1112G>A variant is predicted to result in the amino acid substitution p.Arg371Gln. This variant was reported in an individual with pulmonary arterial hypertension (Supplementary Dataset 1 in Wang et al. 2018. PubMed ID: 30578397) and in a patient with cleft lip with/without cleft palate (Marini et al. 2019. PubMed ID: 31063268). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/4-96069934-G-A). This variant has been interpreted by a single submitter in ClinVar as likely benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/441001/). 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. -

Type A2 brachydactyly;C4225404:Acromesomelic dysplasia 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Type A2 brachydactyly Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;D;.;D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	-0.070	N;N;.;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.81
MVP		0.75
MPC		0.21
ClinPred		0.043	T
GERP RS		5.5
Varity_R		0.84
gMVP		0.85

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: rs34970181; hg19: chr4-96069934; COSMIC: COSV52779885;