17-14074145-G-A

Position:

• chr17-14074145-G-A

Variant summary

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

The NM_001303.4(COX10):​c.44-178G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 151,952 control chromosomes in the GnomAD database, including 12,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.40 (12342 hom., cov: 32)
• Consequence: COX10 NM_001303.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-14074145-G-A is Benign according to our data. Variant chr17-14074145-G-A is described in ClinVar as [Benign]. Clinvar id is 683588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX10	NM_001303.4	c.44-178G>A		intron_variant		ENST00000261643.8	NP_001294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX10	ENST00000261643.8	c.44-178G>A		intron_variant		1	NM_001303.4	ENSP00000261643	P1

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61046 AN: 151834 Hom.: 12329 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.407

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

GnomAD4 genome AF: 0.402 AC: 61092 AN: 151952 Hom.: 12342 Cov.: 32 AF XY: 0.403 AC XY: 29916 AN XY: 74248

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.333

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.489

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.412

Alfa AF: 0.408 Hom.: 25810

Bravo AF: 0.396

Asia WGS AF: 0.461 AC: 1605 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.046
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11870213; hg19: chr17-13977462;