rs12327738

chr19-18784408-G-A

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: -2.25

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=-0.91).
• BP6: Variant 19-18784408-G-A is Benign according to our data. Variant chr19-18784408-G-A is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	UniProt
COMP	NM_000095.3	c.1915-45C>T		intron_variant		ENST00000222271.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMP	ENST00000222271.7	c.1915-45C>T		intron_variant		1	NM_000095.3	P1
COMP	ENST00000542601.6	c.1816-45C>T		intron_variant		1
COMP	ENST00000425807.1	c.1756-45C>T		intron_variant		2

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

GnomAD3 exomes AF: 0.269 AC: 66307 AN: 246460 Hom.: 9570 AF XY: 0.267 AC XY: 35763 AN XY: 133926

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 SAS exome AF: 0.164

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

Gnomad4 AFR exome AF: 0.259

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.0906

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.399

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.278

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

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.0988

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.325

Gnomad4 OTH AF: 0.244

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.032
Dann	Benign	0.55

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: rs12327738; hg19: chr19-18895218;