chr6-55774205-T-C

Variant names:

• chr6-55774205-T-C
• rs995450354
• NM_021073.4:c.871A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021073.4(BMP5):​c.871A>G​(p.Arg291Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BMP5 NM_021073.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

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.871A>G	p.Arg291Gly	missense	Exon 4 of 7	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.871A>G	p.Arg291Gly	missense	Exon 4 of 6	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.871A>G	p.Arg291Gly	missense	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.871A>G	p.Arg291Gly	missense	Exon 4 of 7	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.871A>G	p.Arg291Gly	missense	Exon 4 of 6	ENSP00000571582.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461044 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726838

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111456

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.31
Sift	Benign	0.089	T
Sift4G	Benign	0.20	T
Polyphen		0.11	B
Vest4		0.87
MutPred		0.62		Loss of MoRF binding (P = 0.0263)
MVP		0.67
MPC		0.45
ClinPred		0.92	D
GERP RS		1.8
Varity_R		0.46
gMVP		0.74
Mutation Taster		=19/81	disease causing

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: rs995450354; hg19: chr6-55639003;