rs150008764

Positions:

• chr19-18790128-G-A
• chr19-18790128-G-C
• chr19-18790128-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000095.3(COMP):​c.218-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,520,822 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 31)
  • Exomes 𝑓: 0.017 (247 hom.)
• Consequence: COMP NM_000095.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.623

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-18790128-G-A is Benign according to our data. Variant chr19-18790128-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18790128-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1996/152016) while in subpopulation NFE AF= 0.0197 (1339/67894). AF 95% confidence interval is 0.0188. There are 25 homozygotes in gnomad4. There are 998 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1996 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.218-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.218-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000095.3	P1
COMP	ENST00000542601.6	c.119-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1
COMP	ENST00000425807.1	c.218-14C>T		splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1997 AN: 151898 Hom.: 25 Cov.: 31

Gnomad AFR AF: 0.00363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0129 AC: 1580 AN: 122210 Hom.: 17 AF XY: 0.0130 AC XY: 864 AN XY: 66652

Gnomad AFR exome AF: 0.00262

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.00644

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00745

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0170 AC: 23337 AN: 1368806 Hom.: 247 Cov.: 33 AF XY: 0.0168 AC XY: 11327 AN XY: 673144

Gnomad4 AFR exome AF: 0.00325

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.00592

Gnomad4 EAS exome AF: 0.0000566

Gnomad4 SAS exome AF: 0.00775

Gnomad4 FIN exome AF: 0.0159

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0155

GnomAD4 genome AF: 0.0131 AC: 1996 AN: 152016 Hom.: 25 Cov.: 31 AF XY: 0.0134 AC XY: 998 AN XY: 74314

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.00664

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00863 Hom.: 1

Bravo AF: 0.0119

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2016	- -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Multiple epiphyseal dysplasia type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.93

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: rs150008764; hg19: chr19-18900937;