rs193922900

chr19-18786034-TGTC-Tchr19-18786034-TGTC-TGTCGTCchr19-18786034-TGTC-TGTCGTCGTC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000095.3(COMP):c.1417_1419del(p.Asp473del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COMP NM_000095.3 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-18786034-TGTC-T is Pathogenic according to our data. Variant chr19-18786034-TGTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 40988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18786034-TGTC-T is described in Lovd as [Pathogenic]. Variant chr19-18786034-TGTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.1417_1419del	p.Asp473del	inframe_deletion	13/19	ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.1417_1419del	p.Asp473del	inframe_deletion	13/19	1	NM_000095.3	P1
COMP	ENST00000542601.6	c.1318_1320del	p.Asp440del	inframe_deletion	12/18	1
COMP	ENST00000425807.1	c.1258_1260del	p.Asp420del	inframe_deletion	12/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461476 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 25, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM4 moderate, PM6 moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The in-frame deletion p.D473del in COMP (NM_000095.3) has been observed in individual(s) with pseudoachondroplasia and spondyloepiphyseal dysplasia ( J T Hecht et al, 1995; Jackson et al, 2011; Huang et al, 2018). This variant has been reported to affect COMP protein function ( Chen et al, 2008; Hartley et al, 2013). Additionally, the variant has been reported to ClinVar as Pathogenic. The p.D473del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a aspartic acid at position 473 of the COMP gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The nucleotide c.1417 in COMP is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	This variant, c.1417_1419del, results in the deletion of 1 amino acid(s) of the COMP protein (p.Asp473del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with pseudoachondroplasia and spondyloepiphyseal dysplasia (PMID: 7670471, 21922596, 30138938). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40988). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects COMP function (PMID: 11084047, 17570134, 22006726, 23956175). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2020	Most common pathogenic variant in the COMP gene and has been reported previously in association with pseudoachondroplasia (Hecht et al., 1995; Suleman et al., 2012; Briggs et al., 2014); Published functional studies in mice demonstrate abnormal growth plates with disorganized chondrocyte columns resulting in the development of short-limb dwarfism (Suleman et al., 2012); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32347019, 29309831, 7670471, 24595329, 17570134, 11084047, 22006726, 23956175, 30138938) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 20, 2019	- -

Multiple epiphyseal dysplasia type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 02, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7670471, 17570134, 23956175, 22006726, 11084047] -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs193922900; hg19: chr19-18896844;