6-55759017-T-C

Variant names:

• chr6-55759017-T-C
• NM_021073.4:c.1203A>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.1203A>G​(p.Ile401Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,666 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: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BMP5 NM_021073.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.199
• 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, 0.919

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.1203A>G	p.Ile401Met	missense	Exon 6 of 7	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.1104+1440A>G		intron	N/A	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.1028-3335A>G		intron	N/A	NP_001316685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	ENST00000370830.4	TSL:1 MANE Select	c.1203A>G	p.Ile401Met	missense	Exon 6 of 7	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.1104+1440A>G		intron	N/A	ENSP00000571582.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453666 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723744

African (AFR) AF: 0.00 AC: 0 AN: 33252

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104738

Other (OTH) AF: 0.00 AC: 0 AN: 60118

GnomAD4 genome Cov.: 31

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	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.0090	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.20
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.4	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.76		Gain of catalytic residue at I401 (P = 0.0038)
MVP		0.86
MPC		0.78
ClinPred		0.99	D
GERP RS		-4.4
Varity_R		0.38
gMVP		0.69
Mutation Taster		=42/58	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

hg19: chr6-55623815;