19-18785063-C-T

Variant names:

• chr19-18785063-C-T
• rs312262899
• NM_000095.3:c.1747G>A
• COMP p.Glu583Lys

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000095.3(COMP):​c.1747G>A​(p.Glu583Lys) 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E583Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.93
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• COMP-related skeletal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• multiple epiphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pseudoachondroplasia

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Illumina
• multiple epiphyseal dysplasia type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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, 7 uncertain in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 127 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.78 (below the threshold of 3.09). Trascript score misZ: 1.5018 (below the threshold of 3.09). GenCC associations: The gene is linked to multiple epiphyseal dysplasia type 1, pseudoachondroplasia, COMP-related skeletal dysplasia, multiple epiphyseal dysplasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000095.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMP	NM_000095.3	MANE Select	c.1747G>A	p.Glu583Lys	missense	Exon 16 of 19	NP_000086.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMP	ENST00000222271.7	TSL:1 MANE Select	c.1747G>A	p.Glu583Lys	missense	Exon 16 of 19	ENSP00000222271.2	P49747-1
	COMP	ENST00000542601.6	TSL:1	c.1648G>A	p.Glu550Lys	missense	Exon 15 of 18	ENSP00000439156.2	G3XAP6
	COMP	ENST00000944187.1		c.1747G>A	p.Glu583Lys	missense	Exon 16 of 20	ENSP00000614246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.84
Sift	Benign	0.039	D
Sift4G	Benign	0.085	T
Varity_R		0.81
gMVP		0.81
Mutation Taster		=5/95	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs312262899;

hg19: chr19-18895873;