19-18782914-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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: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):

• COMP-related skeletal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• multiple epiphyseal dysplasia

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

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

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000095.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMP	NM_000095.3	MANE Select	c.*1G>C		3_prime_UTR	Exon 19 of 19	NP_000086.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMP	ENST00000222271.7	TSL:1 MANE Select	c.*1G>C		3_prime_UTR	Exon 19 of 19	ENSP00000222271.2	P49747-1
	COMP	ENST00000542601.6	TSL:1	c.*1G>C		3_prime_UTR	Exon 18 of 18	ENSP00000439156.2	G3XAP6
	COMP	ENST00000944187.1		c.*1G>C		3_prime_UTR	Exon 20 of 20	ENSP00000614246.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Multiple epiphyseal dysplasia type 1 (1)
-	-	1	not specified (1)
-	-	1	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;