17-14069638-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001303.4(COX10):c.33C>T(p.Arg11=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,613,798 control chromosomes in the GnomAD database, including 3,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (291 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3708 hom.)
• Consequence: COX10 NM_001303.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.20

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 17-14069638-C-T is Benign according to our data. Variant chr17-14069638-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.073 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX10	NM_001303.4	c.33C>T	p.Arg11=	synonymous_variant	1/7	ENST00000261643.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX10	ENST00000261643.8	c.33C>T	p.Arg11=	synonymous_variant	1/7	1	NM_001303.4	P1

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8242 AN: 152168 Hom.: 291 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0747

Gnomad OTH AF: 0.0546

GnomAD3 exomes AF: 0.0589 AC: 14639 AN: 248538 Hom.: 557 AF XY: 0.0602 AC XY: 8105 AN XY: 134632

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.0269

Gnomad ASJ exome AF: 0.0572

Gnomad EAS exome AF: 0.0308

Gnomad SAS exome AF: 0.0408

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0715

Gnomad OTH exome AF: 0.0639

GnomAD4 exome AF: 0.0675 AC: 98720 AN: 1461512 Hom.: 3708 Cov.: 33 AF XY: 0.0670 AC XY: 48693 AN XY: 727062

Gnomad4 AFR exome AF: 0.00917

Gnomad4 AMR exome AF: 0.0289

Gnomad4 ASJ exome AF: 0.0590

Gnomad4 EAS exome AF: 0.0258

Gnomad4 SAS exome AF: 0.0405

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.0720

Gnomad4 OTH exome AF: 0.0623

GnomAD4 genome AF: 0.0541 AC: 8240 AN: 152286 Hom.: 291 Cov.: 32 AF XY: 0.0557 AC XY: 4148 AN XY: 74460

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.0434

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.0279

Gnomad4 SAS AF: 0.0371

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.0747

Gnomad4 OTH AF: 0.0540

Alfa AF: 0.0636 Hom.: 417

Bravo AF: 0.0448

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.0668

EpiControl AF: 0.0665

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2014

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. -

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	12
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs8076787; hg19: chr17-13972955; COSMIC: COSV55402628; COSMIC: COSV55402628;