rs41271330

Variant names:

• chr6-55774230-G-A
• rs41271330
• NM_021073.4:c.846C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_021073.4(BMP5):​c.846C>T​(p.Asn282Asn) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.093 (824 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11862 hom.)
• Consequence: BMP5 NM_021073.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.255
• Publications: 16 publications found

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]

BMP5 Gene-Disease associations (from GenCC):

• dysostosis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 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 VariationId is 3060109.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
BMP5	NM_021073.4	c.846C>T	p.Asn282Asn	synonymous_variant	Exon 4 of 7	ENST00000370830.4	NP_066551.1
BMP5	NM_001329754.2	c.846C>T	p.Asn282Asn	synonymous_variant	Exon 4 of 6		NP_001316683.1
BMP5	NM_001329756.2	c.846C>T	p.Asn282Asn	synonymous_variant	Exon 4 of 5		NP_001316685.1
BMP5	XM_011514817.4	c.846C>T	p.Asn282Asn	synonymous_variant	Exon 4 of 5		XP_011513119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP5	ENST00000370830.4	c.846C>T	p.Asn282Asn	synonymous_variant	Exon 4 of 7	1	NM_021073.4	ENSP00000359866.3

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

GnomAD2 exomes AF: 0.112 AC: 28047 AN: 251020 AF XY: 0.109

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 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

African (AFR) AF: 0.0216 AC: 722 AN: 33422

American (AMR) AF: 0.126 AC: 5607 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2826 AN: 26070

East Asian (EAS) AF: 0.142 AC: 5638 AN: 39684

South Asian (SAS) AF: 0.0575 AC: 4955 AN: 86232

European-Finnish (FIN) AF: 0.127 AC: 6758 AN: 53408

Middle Eastern (MID) AF: 0.0313 AC: 178 AN: 5692

European-Non Finnish (NFE) AF: 0.132 AC: 146437 AN: 1110712

Other (OTH) AF: 0.120 AC: 7209 AN: 60310

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

African (AFR) AF: 0.0285 AC: 1181 AN: 41476

American (AMR) AF: 0.0960 AC: 1462 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 373 AN: 3462

East Asian (EAS) AF: 0.169 AC: 869 AN: 5148

South Asian (SAS) AF: 0.0622 AC: 300 AN: 4824

European-Finnish (FIN) AF: 0.119 AC: 1265 AN: 10588

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8450 AN: 67904

Other (OTH) AF: 0.0941 AC: 199 AN: 2114

Alfa AF: 0.111 Hom.: 2289

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: no assertion criteria provided

Submissions by phenotype

BMP5-related disorder Benign:1

Nov 18, 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_noAF	Benign	-0.53
CADD	Benign	0.38
DANN	Benign	0.30
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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