chr6-55759017-T-C

Variant names:

• chr6-55759017-T-C
• NM_021073.4:c.1203A>G

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP5	NM_021073.4	c.1203A>G	p.Ile401Met	missense_variant	Exon 6 of 7	ENST00000370830.4	NP_066551.1
BMP5	NM_001329754.2	c.1104+1440A>G		intron_variant	Intron 5 of 5		NP_001316683.1
BMP5	NM_001329756.2	c.1028-3335A>G		intron_variant	Intron 4 of 4		NP_001316685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP5	ENST00000370830.4	c.1203A>G	p.Ile401Met	missense_variant	Exon 6 of 7	1	NM_021073.4	ENSP00000359866.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1203A>G (p.I401M) alteration is located in exon 6 (coding exon 6) of the BMP5 gene. This alteration results from a A to G substitution at nucleotide position 1203, causing the isoleucine (I) at amino acid position 401 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-55623815;