rs3734444

Variant names:

• chr6-55874755-A-G
• rs3734444
• NM_021073.4:c.111T>C

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.111T>C​(p.Ser37Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,613,042 control chromosomes in the GnomAD database, including 149,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.48 (18626 hom., cov: 30)
  • Exomes 𝑓: 0.42 (131286 hom.)
• Consequence: BMP5 NM_021073.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.30

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-55874755-A-G is Benign according to our data. Variant chr6-55874755-A-G is described in ClinVar as [Benign]. Clinvar id is 3060963.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=2.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP5	NM_021073.4	c.111T>C	p.Ser37Ser	synonymous_variant	Exon 1 of 7	ENST00000370830.4	NP_066551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP5	ENST00000370830.4	c.111T>C	p.Ser37Ser	synonymous_variant	Exon 1 of 7	1	NM_021073.4	ENSP00000359866.3

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73333 AN: 151610 Hom.: 18593 Cov.: 30

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.483

GnomAD2 exomes AF: 0.433 AC: 108676 AN: 250924 AF XY: 0.426

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.419 AC: 611588 AN: 1461316 Hom.: 131286 Cov.: 61 AF XY: 0.417 AC XY: 302974 AN XY: 726972

Gnomad4 AFR exome AF: 0.623 AC: 20836 AN: 33426

Gnomad4 AMR exome AF: 0.511 AC: 22850 AN: 44676

Gnomad4 ASJ exome AF: 0.488 AC: 12756 AN: 26114

Gnomad4 EAS exome AF: 0.169 AC: 6694 AN: 39686

Gnomad4 SAS exome AF: 0.363 AC: 31322 AN: 86250

Gnomad4 FIN exome AF: 0.478 AC: 25519 AN: 53414

Gnomad4 NFE exome AF: 0.416 AC: 462512 AN: 1111626

Gnomad4 Remaining exome AF: 0.432 AC: 26090 AN: 60362

GnomAD4 genome AF: 0.484 AC: 73429 AN: 151726 Hom.: 18626 Cov.: 30 AF XY: 0.485 AC XY: 35933 AN XY: 74098

Gnomad4 AFR AF: 0.608 AC: 0.607916 AN: 0.607916

Gnomad4 AMR AF: 0.519 AC: 0.518862 AN: 0.518862

Gnomad4 ASJ AF: 0.495 AC: 0.494807 AN: 0.494807

Gnomad4 EAS AF: 0.171 AC: 0.170552 AN: 0.170552

Gnomad4 SAS AF: 0.350 AC: 0.350125 AN: 0.350125

Gnomad4 FIN AF: 0.508 AC: 0.507991 AN: 0.507991

Gnomad4 NFE AF: 0.427 AC: 0.426928 AN: 0.426928

Gnomad4 OTH AF: 0.488 AC: 0.488163 AN: 0.488163

Alfa AF: 0.446 Hom.: 39281

Bravo AF: 0.489

Asia WGS AF: 0.299 AC: 1040 AN: 3478

EpiCase AF: 0.437

EpiControl AF: 0.440

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BMP5-related disorder Benign:1

Oct 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	9.1
DANN	Benign	0.78
Mutation Taster		=86/14	polymorphism (auto)

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: rs3734444; hg19: chr6-55739553; COSMIC: COSV63701055;