19-18782900-T-C

Position:

• chr19-18782900-T-C

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.*15A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,610,186 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (12 hom.)
• Consequence: COMP NM_000095.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.340

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 19-18782900-T-C is Benign according to our data. Variant chr19-18782900-T-C is described in ClinVar as [Benign]. Clinvar id is 328608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00142 (216/152180) while in subpopulation SAS AF= 0.00435 (21/4826). AF 95% confidence interval is 0.00292. There are 1 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3	c.*15A>G		3_prime_UTR_variant	19/19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271	c.*15A>G		3_prime_UTR_variant	19/19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601	c.*15A>G		3_prime_UTR_variant	18/18	1		ENSP00000439156.2
COMP	ENST00000425807	c.*15A>G		3_prime_UTR_variant	18/18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152062 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00201 AC: 501 AN: 248748 Hom.: 2 AF XY: 0.00235 AC XY: 317 AN XY: 134972

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00468

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00493

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00263 AC: 3833 AN: 1458006 Hom.: 12 Cov.: 31 AF XY: 0.00273 AC XY: 1978 AN XY: 725500

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00502

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.00270

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152180 Hom.: 1 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74420

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00161

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	5.3
DANN	Benign	0.78

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: rs201937857; hg19: chr19-18893710;