19-18782914-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000095.3(COMP):c.*1G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,611,440 control chromosomes in the GnomAD database, including 1,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (827 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (823 hom.)
• Consequence: COMP NM_000095.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.207

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=-0.72).
• BP6: Variant 19-18782914-C-G is Benign according to our data. Variant chr19-18782914-C-G is described in ClinVar as [Benign]. Clinvar id is 255117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMP	NM_000095.3	c.*1G>C		3_prime_UTR_variant	19/19	ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.*1G>C		3_prime_UTR_variant	19/19	1	NM_000095.3	P1
COMP	ENST00000542601.6	c.*1G>C		3_prime_UTR_variant	18/18	1
COMP	ENST00000425807.1	c.*1G>C		3_prime_UTR_variant	18/18	2

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8825 AN: 152126 Hom.: 820 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0382

GnomAD3 exomes AF: 0.0167 AC: 4168 AN: 249604 Hom.: 336 AF XY: 0.0131 AC XY: 1773 AN XY: 135268

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.00879

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000663

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.00713 AC: 10404 AN: 1459196 Hom.: 823 Cov.: 31 AF XY: 0.00667 AC XY: 4842 AN XY: 726030

Gnomad4 AFR exome AF: 0.213

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000386

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0582 AC: 8860 AN: 152244 Hom.: 827 Cov.: 33 AF XY: 0.0555 AC XY: 4135 AN XY: 74464

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.0378

Alfa AF: 0.0203 Hom.: 74

Bravo AF: 0.0664

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2018

- -

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	-0.72
Cadd	Benign	12
Dann	Benign	0.76

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: rs77185131; hg19: chr19-18893724;