rs41271330

chr6-55774230-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_021073.4(BMP5):c.846C>T(p.Asn282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,612,094 control chromosomes in the GnomAD database, including 12,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.093 (824 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11862 hom.)
• Consequence: BMP5 NM_021073.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.255

Genes affected

BMP5 (HGNC:1072): (bone morphogenetic protein 5) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Polymorphisms in this gene may be associated with osteoarthritis in human patients. This gene is differentially regulated in multiple human cancers. This gene encodes distinct protein isoforms that may be similarly proteolytically processed. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-55774230-G-A is Benign according to our data. Variant chr6-55774230-G-A is described in ClinVar as [Benign]. Clinvar id is 3060109.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.255 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP5	NM_021073.4	c.846C>T	p.Asn282=	synonymous_variant	4/7	ENST00000370830.4
BMP5	NM_001329754.2	c.846C>T	p.Asn282=	synonymous_variant	4/6
BMP5	NM_001329756.2	c.846C>T	p.Asn282=	synonymous_variant	4/5
BMP5	XM_011514817.4	c.846C>T	p.Asn282=	synonymous_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP5	ENST00000370830.4	c.846C>T	p.Asn282=	synonymous_variant	4/7	1	NM_021073.4	P1

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14166 AN: 151836 Hom.: 815 Cov.: 32

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0960

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.0615

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0860

GnomAD3 exomes AF: 0.112 AC: 28047 AN: 251020 Hom.: 1768 AF XY: 0.109 AC XY: 14734 AN XY: 135646

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.0580

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.124 AC: 180330 AN: 1460142 Hom.: 11862 Cov.: 32 AF XY: 0.120 AC XY: 87421 AN XY: 726434

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.0575

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.0934 AC: 14191 AN: 151952 Hom.: 824 Cov.: 32 AF XY: 0.0919 AC XY: 6823 AN XY: 74258

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.0960

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.0622

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.0941

Alfa AF: 0.110 Hom.: 638

Bravo AF: 0.0915

Asia WGS AF: 0.163 AC: 569 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.110

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BMP5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

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_noAF	Benign	-0.53
Cadd	Benign	0.38
Dann	Benign	0.30

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: rs41271330; hg19: chr6-55639028; COSMIC: COSV63707020;