rs1555791556

Positions:

• chr19-18787500-C-A
• chr19-18787500-C-G
• chr19-18787500-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000095.3(COMP):​c.1126G>T​(p.Asp376Tyr) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D376G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.02

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 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-18787499-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2861303.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 19-18787500-C-A is Pathogenic according to our data. Variant chr19-18787500-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438839.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.1126G>T	p.Asp376Tyr	missense_variant	10/19	ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.1126G>T	p.Asp376Tyr	missense_variant	10/19	1	NM_000095.3	P1
COMP	ENST00000542601.6	c.1027G>T	p.Asp343Tyr	missense_variant	9/18	1
COMP	ENST00000425807.1	c.967G>T	p.Asp323Tyr	missense_variant	9/18	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome;C1838280:Multiple epiphyseal dysplasia type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Aug 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-8.2	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.93
MutPred		0.60		.;Loss of sheet (P = 0.0483);.;
MVP		0.93
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.99
gMVP		0.99

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: rs1555791556; hg19: chr19-18898309;