rs77185131

Variant names:

• chr19-18782914-C-G
• rs77185131
• NM_000095.3:c.*1G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-18782914-C-G
• chr19-18782914-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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:5
• Conservation: PhyloP100: 0.207
• Publications: 3 publications found

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]

COMP Gene-Disease associations (from GenCC):

• multiple epiphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pseudoachondroplasia

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina
• multiple epiphyseal dysplasia type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• 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 rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.*1G>C		3_prime_UTR_variant	Exon 19 of 19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.*1G>C		3_prime_UTR_variant	Exon 19 of 19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.*1G>C		3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.*1G>C		3_prime_UTR_variant	Exon 18 of 18	2		ENSP00000403792.1

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

GnomAD2 exomes AF: 0.0167 AC: 4168 AN: 249604 AF XY: 0.0131

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 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

African (AFR) AF: 0.213 AC: 7129 AN: 33428

American (AMR) AF: 0.0107 AC: 477 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 347 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0116 AC: 1000 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51752

Middle Eastern (MID) AF: 0.0137 AC: 69 AN: 5022

European-Non Finnish (NFE) AF: 0.000386 AC: 429 AN: 1111958

Other (OTH) AF: 0.0158 AC: 951 AN: 60284

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

African (AFR) AF: 0.199 AC: 8266 AN: 41504

American (AMR) AF: 0.0214 AC: 328 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68006

Other (OTH) AF: 0.0378 AC: 80 AN: 2116

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 20, 2018

GeneDx

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. -

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	-0.72
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77185131; hg19: chr19-18893724;