4-95051734-A-G

Variant names:

• chr4-95051734-A-G
• rs772207151
• NM_001203.3:c.-17-52674A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001256793.2(BMPR1B):​c.35A>G​(p.His12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,535,476 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (5 hom.)
• Consequence: BMPR1B NM_001256793.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.915

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064976513).
• BP6: Variant 4-95051734-A-G is Benign according to our data. Variant chr4-95051734-A-G is described in ClinVar as [Benign]. Clinvar id is 3035814.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR1B	NM_001203.3	c.-17-52674A>G		intron_variant	Intron 3 of 12	ENST00000515059.6	NP_001194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR1B	ENST00000515059.6	c.-17-52674A>G		intron_variant	Intron 3 of 12	1	NM_001203.3	ENSP00000426617.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00137 AC: 176 AN: 128378 AF XY: 0.00129

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000471 AC: 652 AN: 1383300 Hom.: 5 Cov.: 30 AF XY: 0.000481 AC XY: 328 AN XY: 682550

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31590

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35696

Gnomad4 ASJ exome AF: 0.0183 AC: 461 AN: 25176

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35724

Gnomad4 SAS exome AF: 0.0000505 AC: 4 AN: 79234

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 33464

Gnomad4 NFE exome AF: 0.000118 AC: 127 AN: 1078828

Gnomad4 Remaining exome AF: 0.00102 AC: 59 AN: 57896

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74346

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241208 AN: 0.0000241208

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.0159 AC: 0.0158593 AN: 0.0158593

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000191 AC: 0.000191115 AN: 0.000191115

Gnomad4 OTH AF: 0.000480 AC: 0.000479846 AN: 0.000479846

Alfa AF: 0.00240 Hom.: 0

Bravo AF: 0.000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00229 AC: 35

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BMPR1B-related disorder Benign:1

Jul 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.2
DANN	Benign	0.30
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.18
Sift	Benign	0.32	T
Sift4G	Benign	0.34	T
Vest4		0.16
MVP		0.48
MPC		0.18
ClinPred		0.067	T
GERP RS		-5.0
gMVP		0.31
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs772207151; hg19: chr4-95972885;