chr19-18785047-A-C

Variant names:

• chr19-18785047-A-C
• NM_000095.3:c.1763T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000095.3(COMP):​c.1763T>G​(p.Val588Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.16

Genes affected

COMP (HGNC:2227): (cartilage oligomeric matrix protein) The protein encoded by this gene is a noncollagenous extracellular matrix (ECM) protein. It consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. Oligomerization results from formation of a five-stranded coiled coil and disulfides. Binding to other ECM proteins such as collagen appears to depend on divalent cations. Contraction or expansion of a 5 aa aspartate repeat and other mutations can cause pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain TSP C-terminal (size 214) in uniprot entity COMP_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.1763T>G	p.Val588Gly	missense_variant	Exon 16 of 19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1763T>G	p.Val588Gly	missense_variant	Exon 16 of 19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.1664T>G	p.Val555Gly	missense_variant	Exon 15 of 18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.1604T>G	p.Val535Gly	missense_variant	Exon 15 of 18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.58
MutPred		0.75		.;Loss of stability (P = 0.0012);.;
MVP		0.98
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.95

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: chr19-18895857;