19-18782922-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000095.3(COMP):c.2267A>G(p.Gln756Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,611,810 control chromosomes in the GnomAD database, including 1,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 832 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 824 hom. )

Consequence

COMP
NM_000095.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.269

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025850236).

BP6

Variant 19-18782922-T-C is Benign according to our data. Variant chr19-18782922-T-C is described in ClinVar as [Benign]. Clinvar id is 255124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18782922-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3 linkuse as main transcript	c.2267A>G	p.Gln756Arg	missense_variant	19/19	ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7 linkuse as main transcript	c.2267A>G	p.Gln756Arg	missense_variant	19/19	1	NM_000095.3	P1	P49747-1
COMP	ENST00000542601.6 linkuse as main transcript	c.2168A>G	p.Gln723Arg	missense_variant	18/18	1
COMP	ENST00000425807.1 linkuse as main transcript	c.2108A>G	p.Gln703Arg	missense_variant	18/18	2			P49747-2

Frequencies

GnomAD3 genomes

AF:

0.0581

AC:

8830

AN:

152060

Hom.:

823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0216

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.0378

GnomAD3 exomes

AF:

0.0167

AC:

4171

AN:

249832

Hom.:

336

AF XY:

0.0131

AC XY:

1775

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.202

Gnomad AMR exome

AF:

0.00879

Gnomad ASJ exome

AF:

0.0133

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.00866

GnomAD4 exome

AF:

0.00713

AC:

10414

AN:

1459632

Hom.:

824

Cov.:

AF XY:

0.00667

AC XY:

4844

AN XY:

726250

show subpopulations

Gnomad4 AFR exome

AF:

0.213

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000385

Gnomad4 OTH exome

AF:

0.0158

GnomAD4 genome

AF:

0.0583

AC:

8869

AN:

152178

Hom.:

832

Cov.:

AF XY:

0.0556

AC XY:

4138

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.199

Gnomad4 AMR

AF:

0.0214

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.0374

Alfa

AF:

0.0170

Hom.:

261

Bravo

AF:

0.0664

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.194

AC:

854

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.0198

AC:

2404

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Multiple epiphyseal dysplasia type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

Cadd

Benign

6.9

Dann

Benign

0.72

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.32

T;T;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.42

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.69

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.058

ClinPred

0.000017

GERP RS

-2.6

Varity_R

0.074

gMVP

0.40

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over