rs150008764

chr19-18790128-G-Achr19-18790128-G-Cchr19-18790128-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000095.3(COMP):c.218-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,520,822 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 25 hom., cov: 31)

Exomes 𝑓: 0.017 ( 247 hom. )

Consequence

COMP
NM_000095.3 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.623

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 (BayesDel_noAF=-0.84).

BP6

Variant 19-18790128-G-A is Benign according to our data. Variant chr19-18790128-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18790128-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1996/152016) while in subpopulation NFE AF= 0.0197 (1339/67894). AF 95% confidence interval is 0.0188. There are 25 homozygotes in gnomad4. There are 998 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 1997 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3 linkuse as main transcript	c.218-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7 linkuse as main transcript	c.218-14C>T	splice_polypyrimidine_tract_variant, intron_variant	1	NM_000095.3	P1	P49747-1
COMP	ENST00000542601.6 linkuse as main transcript	c.119-14C>T	splice_polypyrimidine_tract_variant, intron_variant	1
COMP	ENST00000425807.1 linkuse as main transcript	c.218-14C>T	splice_polypyrimidine_tract_variant, intron_variant	2			P49747-2

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1997

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.00664

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.0189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0129

AC:

1580

AN:

122210

Hom.:

AF XY:

0.0130

AC XY:

864

AN XY:

66652

show subpopulations

Gnomad AFR exome

AF:

0.00262

Gnomad AMR exome

AF:

0.0120

Gnomad ASJ exome

AF:

0.00644

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00745

Gnomad FIN exome

AF:

0.0173

Gnomad NFE exome

AF:

0.0204

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0170

AC:

23337

AN:

1368806

Hom.:

247

Cov.:

AF XY:

0.0168

AC XY:

11327

AN XY:

673144

show subpopulations

Gnomad4 AFR exome

AF:

0.00325

Gnomad4 AMR exome

AF:

0.0115

Gnomad4 ASJ exome

AF:

0.00592

Gnomad4 EAS exome

AF:

0.0000566

Gnomad4 SAS exome

AF:

0.00775

Gnomad4 FIN exome

AF:

0.0159

Gnomad4 NFE exome

AF:

0.0192

Gnomad4 OTH exome

AF:

0.0155

GnomAD4 genome

AF:

0.0131

AC:

1996

AN:

152016

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

998

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00361

Gnomad4 AMR

AF:

0.0153

Gnomad4 ASJ

AF:

0.00664

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.0189

Gnomad4 NFE

AF:

0.0197

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00863

Hom.:

Bravo

AF:

0.0119

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2016	- -
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. -

Multiple epiphyseal dysplasia type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

Cadd

Benign

4.6

Dann

Benign

0.93

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