NM_021073.4:c.894A>G

Variant names:

• chr6-55774182-T-C
• rs80225326
• NM_021073.4:c.894A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_021073.4(BMP5):​c.894A>G​(p.Gln298Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00094 in 1,613,070 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (8 hom.)
• Consequence: BMP5 NM_021073.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.154
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-55774182-T-C is Benign according to our data. Variant chr6-55774182-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3038083.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.154 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

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.894A>G	p.Gln298Gln	synonymous	Exon 4 of 7	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.894A>G	p.Gln298Gln	synonymous	Exon 4 of 6	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.894A>G	p.Gln298Gln	synonymous	Exon 4 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.894A>G	p.Gln298Gln	synonymous	Exon 4 of 7	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.894A>G	p.Gln298Gln	synonymous	Exon 4 of 6	ENSP00000571582.1

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 151902 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000825

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00172 AC: 431 AN: 251208 AF XY: 0.00154

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.000907

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000895 AC: 1308 AN: 1461050 Hom.: 8 Cov.: 31 AF XY: 0.000903 AC XY: 656 AN XY: 726844

African (AFR) AF: 0.0000299 AC: 1 AN: 33426

American (AMR) AF: 0.0000448 AC: 2 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.0129 AC: 688 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.000399 AC: 444 AN: 1111458

Other (OTH) AF: 0.00111 AC: 67 AN: 60344

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152020 Hom.: 1 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000810 AC: 55 AN: 67910

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000972 Hom.: 0

Bravo AF: 0.000332

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Likely 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	-0.54
CADD	Benign	1.1
DANN	Benign	0.51
PhyloP100		-0.15
Mutation Taster		=95/5	polymorphism

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: rs80225326; hg19: chr6-55638980;