chr19-18782926-G-A

Position:

chr19-18782926-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1BP4_StrongBP6_ModerateBS1BS2

The NM_000095.3(COMP):c.2263C>T(p.Arg755Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000695 in 1,612,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

COMP
NM_000095.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.59

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 -12 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

BP4

Computational evidence support a benign effect (MetaRNN=0.017842323).

BP6

Variant 19-18782926-G-A is Benign according to our data. Variant chr19-18782926-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1084802.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000276 (42/152308) while in subpopulation AFR AF= 0.000986 (41/41574). AF 95% confidence interval is 0.000747. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3 linkuse as main transcript	c.2263C>T	p.Arg755Trp	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.2263C>T	p.Arg755Trp	missense_variant	19/19	1	NM_000095.3	ENSP00000222271.2	P49747-1
COMP	ENST00000542601.6 linkuse as main transcript	c.2164C>T	p.Arg722Trp	missense_variant	18/18	1		ENSP00000439156.2	G3XAP6
COMP	ENST00000425807.1 linkuse as main transcript	c.2104C>T	p.Arg702Trp	missense_variant	18/18	2		ENSP00000403792.1	P49747-2

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000800

AC:

AN:

249912

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.000865

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000480

AC:

AN:

1459740

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

726254

show subpopulations

Gnomad4 AFR exome

AF:

0.00132

Gnomad4 AMR exome

AF:

0.000134

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000276

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000971

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

.;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

T;T;T

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.1

.;L;.

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.70

.;P;.

Vest4

0.24

MVP

0.66

ClinPred

0.051

GERP RS

4.1

Varity_R

0.39

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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