19-18785055-C-T

Variant names:

• chr19-18785055-C-T
• rs34467947
• NM_000095.3:c.1755G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000095.3(COMP):​c.1755G>A​(p.Thr585Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0617 in 1,613,994 control chromosomes in the GnomAD database, including 3,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T585T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.048 (260 hom., cov: 31)
  • Exomes 𝑓: 0.063 (3358 hom.)
• Consequence: COMP NM_000095.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.27

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-18785055-C-T is Benign according to our data. Variant chr19-18785055-C-T is described in ClinVar as [Benign]. Clinvar id is 255119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.1755G>A	p.Thr585Thr	synonymous_variant	Exon 16 of 19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1755G>A	p.Thr585Thr	synonymous_variant	Exon 16 of 19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.1656G>A	p.Thr552Thr	synonymous_variant	Exon 15 of 18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.1596G>A	p.Thr532Thr	synonymous_variant	Exon 15 of 18	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes AF: 0.0476 AC: 7243 AN: 152050 Hom.: 260 Cov.: 31

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0699

Gnomad OTH AF: 0.0369

GnomAD3 exomes AF: 0.0493 AC: 12397 AN: 251420 Hom.: 485 AF XY: 0.0498 AC XY: 6774 AN XY: 135902

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0157

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0698

Gnomad OTH exome AF: 0.0480

GnomAD4 exome AF: 0.0631 AC: 92281 AN: 1461826 Hom.: 3358 Cov.: 33 AF XY: 0.0617 AC XY: 44866 AN XY: 727218

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0301

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.0716

Gnomad4 OTH exome AF: 0.0492

GnomAD4 genome AF: 0.0476 AC: 7242 AN: 152168 Hom.: 260 Cov.: 31 AF XY: 0.0477 AC XY: 3546 AN XY: 74392

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.0317

Gnomad4 ASJ AF: 0.0306

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.0698

Gnomad4 OTH AF: 0.0365

Alfa AF: 0.0580 Hom.: 158

Bravo AF: 0.0394

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0589

EpiControl AF: 0.0590

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome;C1838280:Multiple epiphyseal dysplasia type 1;C5436916:Carpal tunnel syndrome 2 Benign:1

Aug 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple epiphyseal dysplasia type 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.52
CADD	Benign	2.3
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: rs34467947; hg19: chr19-18895865; COSMIC: COSV55875671; COSMIC: COSV55875671;