rs397515511

Positions:

• chr19-18785676-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Very_Strong PM2 PP3_Strong

The ENST00000222271.7(COMP):​c.1665C>A​(p.Asn555Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COMP ENST00000222271.7 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.564

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 14 ACMG points.

• PS1: Transcript ENST00000222271.7 (COMP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1709017
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3	c.1665C>A	p.Asn555Lys	missense_variant	14/19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1665C>A	p.Asn555Lys	missense_variant	14/19	1	NM_000095.3	ENSP00000222271	P1
COMP	ENST00000542601.6	c.1566C>A	p.Asn522Lys	missense_variant	13/18	1		ENSP00000439156
COMP	ENST00000425807.1	c.1506C>A	p.Asn502Lys	missense_variant	13/18	2		ENSP00000403792

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Multiple epiphyseal dysplasia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.1	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.98
MutPred		0.85		.;Gain of methylation at N555 (P = 0.0183);.;
MVP		0.81
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.92
gMVP		0.88

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: rs397515511; hg19: chr19-18896486;