rs137852652

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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

Scores

13
5
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.75
Variant links:
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]

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ACMG classification

Classification made for transcript

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
COMPNM_000095.3 linkuse as main transcriptc.1024G>T p.Asp342Tyr missense_variant 10/19 ENST00000222271.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COMPENST00000222271.7 linkuse as main transcriptc.1024G>T p.Asp342Tyr missense_variant 10/191 NM_000095.3 P1P49747-1
COMPENST00000542601.6 linkuse as main transcriptc.925G>T p.Asp309Tyr missense_variant 9/181
COMPENST00000425807.1 linkuse as main transcriptc.865G>T p.Asp289Tyr missense_variant 9/182 P49747-2

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
LINK: link

Submissions by phenotype

Epiphyseal dysplasia, multiple, 1, severe Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852652; hg19: chr19-18898411; API