19-18782959-T-C

Variant names:

• chr19-18782959-T-C
• NM_000095.3:c.2230A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000095.3(COMP):​c.2230A>G​(p.Thr744Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,514 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COMP NM_000095.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain TSP C-terminal (size 214) in uniprot entity COMP_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000095.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.2230A>G	p.Thr744Ala	missense_variant, splice_region_variant	Exon 19 of 19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.2230A>G	p.Thr744Ala	missense_variant, splice_region_variant	Exon 19 of 19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.2131A>G	p.Thr711Ala	missense_variant, splice_region_variant	Exon 18 of 18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.2071A>G	p.Thr691Ala	missense_variant, splice_region_variant	Exon 18 of 18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460514 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726600

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;D;.
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.0	.;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.52
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.45	.;B;.
Vest4		0.57
MutPred		0.45		.;Loss of solvent accessibility (P = 0.0435);.;
MVP		0.80
ClinPred		0.91	D
GERP RS		3.1
Varity_R		0.52
gMVP		0.46

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18893769;