10-99712305-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_078470.6(COX15):c.*2282G>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 0.000269 in 985,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

COX15
NM_078470.6 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.39

Variant links:

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]

COX15 links:

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]

CUTC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX15	NM_078470.6 linkuse as main transcript	c.*2282G>A		3_prime_UTR_variant	9/9	ENST00000016171.6

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX15	ENST00000016171.6 linkuse as main transcript	c.*2282G>A	3_prime_UTR_variant	9/9	1	NM_078470.6	P1	Q7KZN9-1
COX15	ENST00000370483.9 linkuse as main transcript	c.*1109G>A	3_prime_UTR_variant	9/9	1			Q7KZN9-2
CUTC	ENST00000493385.5 linkuse as main transcript	n.116+9632C>T	intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000259

AC:

216

AN:

833080

Hom.:

Cov.:

AF XY:

0.000244

AC XY:

AN XY:

384702

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00102

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000273

Gnomad4 OTH exome

AF:

0.000256

GnomAD4 genome

AF:

0.000322

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000371

Hom.:

Bravo

AF:

0.000181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leigh syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

Cadd

Benign

0.51

Dann

Benign

0.61

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over