rs1434536

Positions:

• chr4-95154814-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001203.3(BMPR1B):​c.*141C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,217,530 control chromosomes in the GnomAD database, including 174,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17468 hom., cov: 32)
  • Exomes 𝑓: 0.54 (157456 hom.)
• Consequence: BMPR1B NM_001203.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.887

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 4-95154814-C-T is Benign according to our data. Variant chr4-95154814-C-T is described in ClinVar as [Benign]. Clinvar id is 350131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1B	NM_001203.3	c.*141C>T		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.*141C>T		3_prime_UTR_variant	13/13	1	NM_001203.3	ENSP00000426617.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69230 AN: 151930 Hom.: 17465 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.539 AC: 573933 AN: 1065482 Hom.: 157456 Cov.: 14 AF XY: 0.536 AC XY: 288841 AN XY: 538734

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.652

Gnomad4 ASJ exome AF: 0.604

Gnomad4 EAS exome AF: 0.390

Gnomad4 SAS exome AF: 0.448

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.527

GnomAD4 genome AF: 0.456 AC: 69262 AN: 152048 Hom.: 17468 Cov.: 32 AF XY: 0.459 AC XY: 34121 AN XY: 74308

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.588

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.579

Gnomad4 NFE AF: 0.544

Gnomad4 OTH AF: 0.486

Alfa AF: 0.537 Hom.: 40122

Bravo AF: 0.450

Asia WGS AF: 0.414 AC: 1442 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	This variant is associated with the following publications: (PMID: 24339876, 21556765, 19738052) -

Brachydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

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
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.76

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: rs1434536; hg19: chr4-96075965; COSMIC: COSV52775666; COSMIC: COSV52775666;