17-14069814-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001303.4(COX10):c.43+166T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 151,994 control chromosomes in the GnomAD database, including 4,427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (4427 hom., cov: 32)
• Consequence: COX10 NM_001303.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.652

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-14069814-T-C is Benign according to our data. Variant chr17-14069814-T-C is described in ClinVar as [Benign]. Clinvar id is 669477.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX10	NM_001303.4	c.43+166T>C		intron_variant		ENST00000261643.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX10	ENST00000261643.8	c.43+166T>C		intron_variant		1	NM_001303.4	P1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35938 AN: 151876 Hom.: 4415 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.246

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

GnomAD4 genome AF: 0.237 AC: 35986 AN: 151994 Hom.: 4427 Cov.: 32 AF XY: 0.240 AC XY: 17861 AN XY: 74316

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.249

Alfa AF: 0.253 Hom.: 10039

Bravo AF: 0.229

Asia WGS AF: 0.231 AC: 800 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.86
Cadd	Benign	4.5
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2302107; hg19: chr17-13973131; COSMIC: COSV55405687; COSMIC: COSV55405687;