rs137852652

Positions:

• chr19-18787602-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000095.3(COMP):​c.1024G>T​(p.Asp342Tyr) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.75

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 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 19-18787602-C-A is Pathogenic according to our data. Variant chr19-18787602-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 9187.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-18787602-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.1024G>T	p.Asp342Tyr	missense_variant	10/19	ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.1024G>T	p.Asp342Tyr	missense_variant	10/19	1	NM_000095.3	P1
COMP	ENST00000542601.6	c.925G>T	p.Asp309Tyr	missense_variant	9/18	1
COMP	ENST00000425807.1	c.865G>T	p.Asp289Tyr	missense_variant	9/18	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epiphyseal dysplasia, multiple, 1, severe Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.4	.;H;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-8.2	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.96
MutPred		0.76		.;Gain of phosphorylation at D342 (P = 0.0264);.;
MVP		0.96
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.96
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs137852652; hg19: chr19-18898411;