17-14069494-G-A

Variant summary

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

The ENST00000602743.1(COX10-DT):n.2C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,313,458 control chromosomes in the GnomAD database, including 655,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75418 hom., cov: 32)
  • Exomes 𝑓: 1.0 (580027 hom.)
• Consequence: COX10-DT ENST00000602743.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.180

Genes affected

COX10-DT (HGNC:38873): (COX10 divergent transcript)

COX10 (HGNC:2260): (cytochrome c oxidase assembly factor heme A:farnesyltransferase COX10) 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 heme A:farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. This protein is predicted to contain 7-9 transmembrane domains localized in the mitochondrial inner membrane. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-14069494-G-A is Benign according to our data. Variant chr17-14069494-G-A is described in ClinVar as [Benign]. Clinvar id is 321803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX10	NM_001303.4			upstream_gene_variant		ENST00000261643.8
COX10-DT	NR_049718.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX10	ENST00000261643.8			upstream_gene_variant		1	NM_001303.4	P1
COX10-DT	ENST00000582752.7			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.995 AC: 151428 AN: 152150 Hom.: 75361 Cov.: 32

Gnomad AFR AF: 0.983

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.995

GnomAD4 exome AF: 1.00 AC: 1160619 AN: 1161190 Hom.: 580027 Cov.: 15 AF XY: 1.00 AC XY: 585791 AN XY: 586032

Gnomad4 AFR exome AF: 0.982

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.999

GnomAD4 genome AF: 0.995 AC: 151544 AN: 152268 Hom.: 75418 Cov.: 32 AF XY: 0.996 AC XY: 74120 AN XY: 74446

Gnomad4 AFR AF: 0.983

Gnomad4 AMR AF: 0.999

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.995

Alfa AF: 0.998 Hom.: 11466

Bravo AF: 0.994

Asia WGS AF: 0.999 AC: 3475 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	13
Dann	Benign	0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6502330; hg19: chr17-13972811;