rs137852655

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000095.3(COMP):​c.2156G>A​(p.Gly719Asp) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G719S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

COMP
NM_000095.3 missense

Scores

17
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a strand (size 12) in uniprot entity COMP_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000095.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-18783126-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 19-18783125-C-T is Pathogenic according to our data. Variant chr19-18783125-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18783125-C-T is described in Lovd as [Pathogenic]. Variant chr19-18783125-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COMPNM_000095.3 linkuse as main transcriptc.2156G>A p.Gly719Asp missense_variant 18/19 ENST00000222271.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COMPENST00000222271.7 linkuse as main transcriptc.2156G>A p.Gly719Asp missense_variant 18/191 NM_000095.3 P1P49747-1
COMPENST00000542601.6 linkuse as main transcriptc.2057G>A p.Gly686Asp missense_variant 17/181
COMPENST00000425807.1 linkuse as main transcriptc.1997G>A p.Gly666Asp missense_variant 17/182 P49747-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsJul 18, 2021- -
Pseudoachondroplasia, severe Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 22, 2001- -
Multiple epiphyseal dysplasia type 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
.;D;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
.;M;.
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-6.6
D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.98
MutPred
0.98
.;Loss of methylation at R718 (P = 0.0386);.;
MVP
0.95
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.96
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs137852655; hg19: chr19-18893935; API