rs12327738

Variant names:

• chr19-18784408-G-A
• rs12327738
• NM_000095.3:c.1915-45C>T

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.1915-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,609,758 control chromosomes in the GnomAD database, including 75,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6554 hom., cov: 31)
  • Exomes 𝑓: 0.30 (68460 hom.)
• Consequence: COMP NM_000095.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.25
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-18784408-G-A is Benign according to our data. Variant chr19-18784408-G-A is described in ClinVar as Benign. ClinVar VariationId is 255121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.1915-45C>T		intron_variant	Intron 16 of 18	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1915-45C>T		intron_variant	Intron 16 of 18	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.1816-45C>T		intron_variant	Intron 15 of 17	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.1756-45C>T		intron_variant	Intron 15 of 17	2		ENSP00000403792.1

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43388 AN: 151926 Hom.: 6555 Cov.: 31

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.0988

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.269 AC: 66307 AN: 246460 AF XY: 0.267

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.0965

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.300 AC: 437198 AN: 1457714 Hom.: 68460 Cov.: 32 AF XY: 0.296 AC XY: 214492 AN XY: 725212

African (AFR) AF: 0.259 AC: 8666 AN: 33404

American (AMR) AF: 0.223 AC: 9959 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 6012 AN: 26106

East Asian (EAS) AF: 0.0906 AC: 3593 AN: 39642

South Asian (SAS) AF: 0.165 AC: 14161 AN: 86080

European-Finnish (FIN) AF: 0.399 AC: 20943 AN: 52548

Middle Eastern (MID) AF: 0.207 AC: 1166 AN: 5622

European-Non Finnish (NFE) AF: 0.321 AC: 355963 AN: 1109512

Other (OTH) AF: 0.278 AC: 16735 AN: 60230

GnomAD4 genome AF: 0.285 AC: 43389 AN: 152044 Hom.: 6554 Cov.: 31 AF XY: 0.283 AC XY: 21063 AN XY: 74320

African (AFR) AF: 0.255 AC: 10578 AN: 41452

American (AMR) AF: 0.245 AC: 3745 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3468

East Asian (EAS) AF: 0.0988 AC: 511 AN: 5170

South Asian (SAS) AF: 0.144 AC: 693 AN: 4820

European-Finnish (FIN) AF: 0.403 AC: 4257 AN: 10558

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22065 AN: 67966

Other (OTH) AF: 0.244 AC: 516 AN: 2116

Alfa AF: 0.297 Hom.: 1421

Bravo AF: 0.270

Asia WGS AF: 0.133 AC: 464 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.032
DANN	Benign	0.55
PhyloP100		-2.3
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: rs12327738; hg19: chr19-18895218; COSMIC: COSV107292369; COSMIC: COSV107292369;