chr19-18783128-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP3_ModerateBS2

The NM_000095.3(COMP):​c.2153G>A​(p.Arg718Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000559 in 1,611,012 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R718P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

COMP
NM_000095.3 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.78
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 Uncertain_significance. Variant got 2 ACMG points.

PM1
In a disulfide_bond (size 221) in uniprot entity COMP_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000095.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-18783128-C-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.874
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COMPNM_000095.3 linkc.2153G>A p.Arg718Gln missense_variant Exon 18 of 19 ENST00000222271.7 NP_000086.2 P49747-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COMPENST00000222271.7 linkc.2153G>A p.Arg718Gln missense_variant Exon 18 of 19 1 NM_000095.3 ENSP00000222271.2 P49747-1
COMPENST00000542601.6 linkc.2054G>A p.Arg685Gln missense_variant Exon 17 of 18 1 ENSP00000439156.2 G3XAP6
COMPENST00000425807.1 linkc.1994G>A p.Arg665Gln missense_variant Exon 17 of 18 2 ENSP00000403792.1 P49747-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152240
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248064
Hom.:
0
AF XY:
0.00000744
AC XY:
1
AN XY:
134498
show subpopulations
Gnomad AFR exome
AF:
0.0000619
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000546
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1458772
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
725756
show subpopulations
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:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152240
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 19, 2024This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 718 of the COMP protein (p.Arg718Gln). This variant is present in population databases (rs149551600, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COMP-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COMP protein function with a negative predictive value of 80%. This variant disrupts the p.Arg718 amino acid residue in COMP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12483304, 14684695, 21834907, 21965141). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.044
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.84
.;D;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Pathogenic
0.51
D
MetaRNN
Pathogenic
0.87
D;D;D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Benign
1.1
.;L;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.1
D;D;D
REVEL
Pathogenic
0.74
Sift
Benign
0.094
T;T;T
Sift4G
Benign
0.26
T;T;T
Polyphen
1.0
.;D;.
Vest4
0.74
MVP
0.86
ClinPred
0.96
D
GERP RS
3.6
Varity_R
0.43
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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: rs149551600; hg19: chr19-18893938; COSMIC: COSV55875712; COSMIC: COSV55875712; API