Variant 19-18782947-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_000095.3(COMP):c.2242G>A(p.Asp748Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,446 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 (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

COMP
NM_000095.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07

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]

COMP links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a region_of_interest Mediates cell survival and induction of the IAP family of survival proteins (size 230) in uniprot entity COMP_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000095.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3 linkuse as main transcript	c.2242G>A	p.Asp748Asn	missense_variant	19/19	ENST00000222271.7	NP_000086.2	P49747-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COMP	ENST00000222271.7 linkuse as main transcript	c.2242G>A	p.Asp748Asn	missense_variant	19/19	1	NM_000095.3	ENSP00000222271.2	P49747-1
COMP	ENST00000542601.6 linkuse as main transcript	c.2143G>A	p.Asp715Asn	missense_variant	18/18	1		ENSP00000439156.2	G3XAP6
COMP	ENST00000425807.1 linkuse as main transcript	c.2083G>A	p.Asp695Asn	missense_variant	18/18	2		ENSP00000403792.1	P49747-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460446

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726588

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2022

ClinVar contains an entry for this variant (Variation ID: 1383008). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COMP protein function. This variant has not been reported in the literature in individuals affected with COMP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 748 of the COMP protein (p.Asp748Asn). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.0033

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

.;D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.4

.;M;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.029

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.64

MutPred

0.18

.;Loss of disorder (P = 0.1558);.;

MVP

0.83

ClinPred

0.99

GERP RS

3.6

Varity_R

0.66

gMVP

0.72

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over