19-18789177-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

multiple epiphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pseudoachondroplasia
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina
multiple epiphyseal dysplasia type 1
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

COMP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 127 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.78 (below the threshold of 3.09). Trascript score misZ: 1.5018 (below the threshold of 3.09). GenCC associations: The gene is linked to pseudoachondroplasia, multiple epiphyseal dysplasia type 1, multiple epiphyseal dysplasia.

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 VariationId is 197627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
COMP	NM_000095.3 link	c.511G>A	p.Ala171Thr	missense_variant	Exon 5 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.511G>A	p.Ala171Thr	missense_variant	Exon 5 of 19	1	NM_000095.3	ENSP00000222271.2	P49747-1
COMP	ENST00000542601.6 link	c.412G>A	p.Ala138Thr	missense_variant	Exon 4 of 18	1		ENSP00000439156.2	G3XAP6
COMP	ENST00000425807.1 link	c.391-285G>A		intron_variant	Intron 4 of 17	2		ENSP00000403792.1	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

GnomAD2 exomes

AF:

0.00463

AC:

974

AN:

210202

AF XY:

0.00337

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 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

African (AFR)

AF:

0.0574

AC:

1817

AN:

31628

American (AMR)

AF:

0.00339

AC:

125

AN:

36880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23710

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39130

South Asian (SAS)

AF:

0.0000621

AC:

AN:

80566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51280

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

0.0000919

AC:

101

AN:

1099284

Other (OTH)

AF:

0.00364

AC:

214

AN:

58798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0170

AC:

2595

AN:

152322

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1220

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0586

AC:

2437

AN:

41568

American (AMR)

AF:

0.00797

AC:

122

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68030

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00348

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

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 11, 2018

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

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome

Benign: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. -

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

Benign:1

Apr 05, 2022

Fulgent Genetics, Fulgent Genetics

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

Oct 30, 2020

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

0.73

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

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

PhyloP100

6.0

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

Mutation Taster

=75/25

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over