17-14210963-G-A

Variant names:

• chr17-14210963-G-A
• rs7211577
• ENST00000458492.1:n.79-325G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000458492.1(COX10):​n.79-325G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 151,904 control chromosomes in the GnomAD database, including 18,870 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (18870 hom., cov: 31)
• Consequence: COX10 ENST00000458492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial complex IV deficiency, nuclear type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX10	ENST00000458492.1	n.79-325G>A		intron_variant	Intron 1 of 2	1
COX10	ENST00000664217.1	n.*837-325G>A		intron_variant	Intron 10 of 13			ENSP00000499396.1
COX10	ENST00000670279.1	n.*536-325G>A		intron_variant	Intron 8 of 10			ENSP00000499450.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 74969 AN: 151786 Hom.: 18879 Cov.: 31

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.505

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.494 AC: 74979 AN: 151904 Hom.: 18870 Cov.: 31 AF XY: 0.495 AC XY: 36755 AN XY: 74254

African (AFR) AF: 0.465 AC: 19264 AN: 41390

American (AMR) AF: 0.389 AC: 5951 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1648 AN: 3462

East Asian (EAS) AF: 0.541 AC: 2782 AN: 5146

South Asian (SAS) AF: 0.619 AC: 2981 AN: 4814

European-Finnish (FIN) AF: 0.569 AC: 6016 AN: 10564

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.508 AC: 34544 AN: 67936

Other (OTH) AF: 0.505 AC: 1066 AN: 2110

Alfa AF: 0.506 Hom.: 14664

Bravo AF: 0.477

Asia WGS AF: 0.536 AC: 1866 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.33
PhyloP100		-0.12

Splicing

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

Other links and lift over

dbSNP: rs7211577; hg19: chr17-14114280; COSMIC: COSV55403776;