chr6-55874755-A-G

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
• Publications: 29 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 6-55874755-A-G is Benign according to our data. Variant chr6-55874755-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021073.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	NM_021073.4	MANE Select	c.111T>C	p.Ser37Ser	synonymous	Exon 1 of 7	NP_066551.1
	BMP5	NM_001329754.2		c.111T>C	p.Ser37Ser	synonymous	Exon 1 of 6	NP_001316683.1
	BMP5	NM_001329756.2		c.111T>C	p.Ser37Ser	synonymous	Exon 1 of 5	NP_001316685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	ENST00000370830.4	TSL:1 MANE Select	c.111T>C	p.Ser37Ser	synonymous	Exon 1 of 7	ENSP00000359866.3
	BMP5	ENST00000901523.1		c.111T>C	p.Ser37Ser	synonymous	Exon 1 of 6	ENSP00000571582.1

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

African (AFR) AF: 0.623 AC: 20836 AN: 33426

American (AMR) AF: 0.511 AC: 22850 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 12756 AN: 26114

East Asian (EAS) AF: 0.169 AC: 6694 AN: 39686

South Asian (SAS) AF: 0.363 AC: 31322 AN: 86250

European-Finnish (FIN) AF: 0.478 AC: 25519 AN: 53414

Middle Eastern (MID) AF: 0.522 AC: 3009 AN: 5762

European-Non Finnish (NFE) AF: 0.416 AC: 462512 AN: 1111626

Other (OTH) 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

African (AFR) AF: 0.608 AC: 25158 AN: 41384

American (AMR) AF: 0.519 AC: 7895 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1715 AN: 3466

East Asian (EAS) AF: 0.171 AC: 878 AN: 5148

South Asian (SAS) AF: 0.350 AC: 1682 AN: 4804

European-Finnish (FIN) AF: 0.508 AC: 5340 AN: 10512

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28979 AN: 67878

Other (OTH) AF: 0.488 AC: 1031 AN: 2112

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	BMP5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.1
DANN	Benign	0.78
PhyloP100		2.3
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

Other links and lift over

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