17-14069497-G-A

Variant summary

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

The ENST00000429152.6(COX10):c.-109G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,350,670 control chromosomes in the GnomAD database, including 22,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1929 hom., cov: 32)
  • Exomes 𝑓: 0.18 (20170 hom.)
• Consequence: COX10 ENST00000429152.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.55

Genes affected

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]

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-14069497-G-A is Benign according to our data. Variant chr17-14069497-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 321804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.185 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: 0.152 AC: 23077 AN: 152082 Hom.: 1928 Cov.: 32

Gnomad AFR AF: 0.0925

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.179 AC: 214310 AN: 1198470 Hom.: 20170 Cov.: 16 AF XY: 0.178 AC XY: 107554 AN XY: 603838

Gnomad4 AFR exome AF: 0.0883

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.0896

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.152 AC: 23086 AN: 152200 Hom.: 1929 Cov.: 32 AF XY: 0.153 AC XY: 11383 AN XY: 74412

Gnomad4 AFR AF: 0.0923

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.152

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.164

Alfa AF: 0.171 Hom.: 277

Bravo AF: 0.147

Asia WGS AF: 0.132 AC: 459 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leigh syndrome Benign:1

Likely 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 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.062
Dann	Benign	0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28680987; hg19: chr17-13972814;