4-95155662-A-G

Position:

• chr4-95155662-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001203.3(BMPR1B):​c.*989A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 151,436 control chromosomes in the GnomAD database, including 29,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (29975 hom., cov: 27)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: BMPR1B NM_001203.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.311

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-95155662-A-G is Benign according to our data. Variant chr4-95155662-A-G is described in ClinVar as [Benign]. Clinvar id is 350147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1B	NM_001203.3	c.*989A>G		3_prime_UTR_variant	13/13	ENST00000515059.6	NP_001194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1B	ENST00000515059.6	c.*989A>G		3_prime_UTR_variant	13/13	1	NM_001203.3	ENSP00000426617	P4
BMPR1B	ENST00000440890.7	c.*989A>G		3_prime_UTR_variant	11/11	2		ENSP00000401907	A1
BMPR1B	ENST00000672698.1	c.*989A>G		3_prime_UTR_variant	13/13			ENSP00000500035	P4
BMPR1B	ENST00000509540.6	c.*13+976A>G		intron_variant		2		ENSP00000421671	P4

Frequencies

GnomAD3 genomes AF: 0.626 AC: 94711 AN: 151318 Hom.: 29931 Cov.: 27

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.694

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.649

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

GnomAD4 genome AF: 0.626 AC: 94810 AN: 151434 Hom.: 29975 Cov.: 27 AF XY: 0.624 AC XY: 46167 AN XY: 73944

Gnomad4 AFR AF: 0.697

Gnomad4 AMR AF: 0.694

Gnomad4 ASJ AF: 0.714

Gnomad4 EAS AF: 0.430

Gnomad4 SAS AF: 0.480

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.591

Gnomad4 OTH AF: 0.651

Alfa AF: 0.600 Hom.: 13789

Bravo AF: 0.640

Asia WGS AF: 0.510 AC: 1775 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Brachydactyly 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	-0.90
CADD	Benign	1.4
DANN	Benign	0.41

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

Other links and lift over

dbSNP: rs11097457; hg19: chr4-96076813;