rs35359254

chr19-18790809-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000095.3(COMP):c.165+41G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,558,104 control chromosomes in the GnomAD database, including 9,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2321 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7623 hom.)
• Consequence: COMP NM_000095.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.590

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-18790809-C-G is Benign according to our data. Variant chr19-18790809-C-G is described in ClinVar as [Benign]. Clinvar id is 255118.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.165+41G>C		intron_variant		ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.165+41G>C		intron_variant		1	NM_000095.3	P1
COMP	ENST00000542601.6	c.66+41G>C		intron_variant		1
COMP	ENST00000425807.1	c.165+41G>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22223 AN: 152086 Hom.: 2310 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0857

Gnomad ASJ AF: 0.0773

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.0849 AC: 13525 AN: 159334 Hom.: 890 AF XY: 0.0809 AC XY: 7051 AN XY: 87106

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0824

Gnomad EAS exome AF: 0.00546

Gnomad SAS exome AF: 0.0263

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0803

GnomAD4 exome AF: 0.0958 AC: 134656 AN: 1405900 Hom.: 7623 Cov.: 34 AF XY: 0.0930 AC XY: 64739 AN XY: 695836

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.0518

Gnomad4 ASJ exome AF: 0.0843

Gnomad4 EAS exome AF: 0.00865

Gnomad4 SAS exome AF: 0.0246

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.0984

Gnomad4 OTH exome AF: 0.0935

GnomAD4 genome AF: 0.146 AC: 22267 AN: 152204 Hom.: 2321 Cov.: 32 AF XY: 0.142 AC XY: 10604 AN XY: 74422

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.0855

Gnomad4 ASJ AF: 0.0773

Gnomad4 EAS AF: 0.00561

Gnomad4 SAS AF: 0.0244

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.0991

Gnomad4 OTH AF: 0.114

Alfa AF: 0.113 Hom.: 230

Bravo AF: 0.150

Asia WGS AF: 0.0420 AC: 145 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	4.7
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35359254; hg19: chr19-18901618;