rs115338183

Positions:

chr19-18789177-C-T

Variant summary

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

The NM_000095.3(COMP):c.511G>A(p.Ala171Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,579,168 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 64 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 62 hom. )

Consequence

COMP
NM_000095.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.01

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=0.00695318).

BP6

Variant 19-18789177-C-T is Benign according to our data. Variant chr19-18789177-C-T is described in ClinVar as [Benign]. Clinvar id is 197627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18789177-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3 linkuse as main transcript	c.511G>A	p.Ala171Thr	missense_variant	5/19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7 linkuse as main transcript	c.511G>A	p.Ala171Thr	missense_variant	5/19	1	NM_000095.3	ENSP00000222271	P1	P49747-1
COMP	ENST00000542601.6 linkuse as main transcript	c.412G>A	p.Ala138Thr	missense_variant	4/18	1		ENSP00000439156
COMP	ENST00000425807.1 linkuse as main transcript	c.391-285G>A		intron_variant		2		ENSP00000403792		P49747-2

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2582

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0585

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00463

AC:

974

AN:

210202

Hom.:

AF XY:

0.00337

AC XY:

389

AN XY:

115526

show subpopulations

Gnomad AFR exome

AF:

0.0619

Gnomad AMR exome

AF:

0.00294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000624

Gnomad SAS exome

AF:

0.0000827

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000113

Gnomad OTH exome

AF:

0.00142

GnomAD4 exome

AF:

0.00160

AC:

2290

AN:

1426846

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1052

AN XY:

709182

show subpopulations

Gnomad4 AFR exome

AF:

0.0574

Gnomad4 AMR exome

AF:

0.00339

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000621

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000919

Gnomad4 OTH exome

AF:

0.00364

GnomAD4 genome

AF:

0.0170

AC:

2595

AN:

152322

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1220

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0586

Gnomad4 AMR

AF:

0.00797

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00371

Hom.:

Bravo

AF:

0.0192

ESP6500AA

AF:

0.0582

AC:

255

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00552

AC:

668

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome;C1838280:Multiple epiphyseal dysplasia type 1;C5436916:Carpal tunnel syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2022

- -

Multiple epiphyseal dysplasia type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

.;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.1

.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.60

Sift

Benign

0.035

D;D

Sift4G

Benign

0.084

T;T

Polyphen

1.0

.;D

Vest4

0.60

MVP

0.79

ClinPred

0.039

GERP RS

3.0

Varity_R

0.55

gMVP

0.60

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