10-99711938-C-T

Position:

• chr10-99711938-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000016171.6(COX15):​c.*2649G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 571,726 control chromosomes in the GnomAD database, including 23,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5759 hom., cov: 32)
  • Exomes 𝑓: 0.29 (18219 hom.)
• Consequence: COX15 ENST00000016171.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0840

Genes affected

COX15 (HGNC:2263): (cytochrome c oxidase assembly homolog COX15) Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes a protein which is not a structural subunit, but may be essential for the biogenesis of COX formation and may function in the hydroxylation of heme O, according to the yeast mutant studies. This protein is predicted to contain 5 transmembrane domains localized in the mitochondrial inner membrane. Alternative splicing of this gene generates two transcript variants diverging in the 3' region. [provided by RefSeq, Jul 2008]

CUTC (HGNC:24271): (cutC copper transporter) Members of the CUT family of copper transporters are associated with copper homeostasis and are involved in the uptake, storage, delivery, and efflux of copper (Gupta et al., 1995 [PubMed 7635807]; Li et al., 2005 [PubMed 16182249]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 10-99711938-C-T is Benign according to our data. Variant chr10-99711938-C-T is described in ClinVar as [Benign]. Clinvar id is 298394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX15	NM_078470.6	c.*2649G>A		3_prime_UTR_variant	9/9	ENST00000016171.6	NP_510870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX15	ENST00000016171.6	c.*2649G>A		3_prime_UTR_variant	9/9	1	NM_078470.6	ENSP00000016171	P1
COX15	ENST00000370483.9	c.*1476G>A		3_prime_UTR_variant	9/9	1		ENSP00000359514
CUTC	ENST00000493385.5	n.116+9265C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41425 AN: 151882 Hom.: 5760 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.290 AC: 121717 AN: 419726 Hom.: 18219 Cov.: 6 AF XY: 0.290 AC XY: 57510 AN XY: 198468

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.340

Gnomad4 NFE exome AF: 0.296

Gnomad4 OTH exome AF: 0.279

GnomAD4 genome AF: 0.273 AC: 41439 AN: 152000 Hom.: 5759 Cov.: 32 AF XY: 0.274 AC XY: 20328 AN XY: 74278

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.355

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.238

Alfa AF: 0.205 Hom.: 475

Bravo AF: 0.260

Asia WGS AF: 0.215 AC: 751 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.7
DANN	Benign	0.71

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1128642; hg19: chr10-101471695;