NM_000095.3:c.1156A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000095.3(COMP):c.1156A>G(p.Asn386Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,613,698 control chromosomes in the GnomAD database, including 1,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 104 hom., cov: 31)

Exomes 𝑓: 0.046 ( 1706 hom. )

Consequence

COMP
NM_000095.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 7.88

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 -18 ACMG points.

PM1

In a region_of_interest Disordered (size 205) in uniprot entity COMP_HUMAN there are 109 pathogenic changes around while only 1 benign (99%) in NM_000095.3

BP4

Computational evidence support a benign effect (MetaRNN=0.014269739).

BP6

Variant 19-18786630-T-C is Benign according to our data. Variant chr19-18786630-T-C is described in ClinVar as [Benign]. Clinvar id is 40987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18786630-T-C is described in Lovd as [Benign]. Variant chr19-18786630-T-C is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3 link	c.1156A>G	p.Asn386Asp	missense_variant	Exon 11 of 19	ENST00000222271.7	NP_000086.2	P49747-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COMP	ENST00000222271.7 link	c.1156A>G	p.Asn386Asp	missense_variant	Exon 11 of 19	1	NM_000095.3	ENSP00000222271.2	P49747-1
COMP	ENST00000542601.6 link	c.1057A>G	p.Asn353Asp	missense_variant	Exon 10 of 18	1		ENSP00000439156.2	G3XAP6
COMP	ENST00000425807.1 link	c.997A>G	p.Asn333Asp	missense_variant	Exon 10 of 18	2		ENSP00000403792.1	P49747-2
COMP	ENST00000612179.1 link	n.406A>G		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0315

AC:

4794

AN:

152076

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00942

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0279

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0372

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0488

Gnomad OTH

AF:

0.0307

GnomAD3 exomes

AF:

0.0329

AC:

8278

AN:

251324

Hom.:

172

AF XY:

0.0346

AC XY:

4698

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00893

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.0310

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0368

Gnomad FIN exome

AF:

0.0294

Gnomad NFE exome

AF:

0.0462

Gnomad OTH exome

AF:

0.0352

GnomAD4 exome

AF:

0.0458

AC:

66940

AN:

1461504

Hom.:

1706

Cov.:

AF XY:

0.0457

AC XY:

33217

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.00681

Gnomad4 AMR exome

AF:

0.0182

Gnomad4 ASJ exome

AF:

0.0289

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0367

Gnomad4 FIN exome

AF:

0.0303

Gnomad4 NFE exome

AF:

0.0517

Gnomad4 OTH exome

AF:

0.0438

GnomAD4 genome

AF:

0.0315

AC:

4789

AN:

152194

Hom.:

104

Cov.:

AF XY:

0.0299

AC XY:

2225

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00939

Gnomad4 AMR

AF:

0.0278

Gnomad4 ASJ

AF:

0.0366

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0372

Gnomad4 FIN

AF:

0.0261

Gnomad4 NFE

AF:

0.0487

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0429

Hom.:

185

Bravo

AF:

0.0305

TwinsUK

AF:

0.0520

AC:

193

ALSPAC

AF:

0.0576

AC:

222

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.0473

AC:

407

ExAC

AF:

0.0338

AC:

4099

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0443

EpiControl

AF:

0.0458

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome

Benign:1Other:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple epiphyseal dysplasia type 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Connective tissue disorder

Benign:1

Apr 23, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Pathogenic

4.2

.;H;.

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.022

D;D;T

Polyphen

1.0

.;D;.

Vest4

0.28

ClinPred

0.041

GERP RS

3.4

Varity_R

0.96

gMVP

0.88

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