rs114521946

Variant names:

• chr17-14159934-C-T
• rs114521946
• NM_001303.4:c.682C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001303.4(COX10):​c.682C>T​(p.Arg228Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,612,150 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (12 hom.)
• Consequence: COX10 NM_001303.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.88
• 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001303.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.018391252).
• BP6: Variant 17-14159934-C-T is Benign according to our data. Variant chr17-14159934-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137010.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0067 (1019/152200) while in subpopulation AFR AF = 0.0231 (961/41526). AF 95% confidence interval is 0.0219. There are 10 homozygotes in GnomAd4. There are 460 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX10	NM_001303.4	MANE Select	c.682C>T	p.Arg228Cys	missense	Exon 5 of 7	NP_001294.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX10	ENST00000261643.8	TSL:1 MANE Select	c.682C>T	p.Arg228Cys	missense	Exon 5 of 7	ENSP00000261643.3
	COX10	ENST00000886734.1		c.271C>T	p.Arg91Cys	missense	Exon 4 of 6	ENSP00000556793.1
	COX10	ENST00000886735.1		c.235C>T	p.Arg79Cys	missense	Exon 3 of 5	ENSP00000556794.1

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1015 AN: 152082 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00184 AC: 459 AN: 249804 AF XY: 0.00136

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.000813

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000717 AC: 1047 AN: 1459950 Hom.: 12 Cov.: 30 AF XY: 0.000614 AC XY: 446 AN XY: 726206

African (AFR) AF: 0.0232 AC: 774 AN: 33434

American (AMR) AF: 0.00110 AC: 49 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000588 AC: 3 AN: 5104

European-Non Finnish (NFE) AF: 0.0000864 AC: 96 AN: 1111400

Other (OTH) AF: 0.00139 AC: 84 AN: 60262

GnomAD4 genome AF: 0.00670 AC: 1019 AN: 152200 Hom.: 10 Cov.: 33 AF XY: 0.00618 AC XY: 460 AN XY: 74404

African (AFR) AF: 0.0231 AC: 961 AN: 41526

American (AMR) AF: 0.00223 AC: 34 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00222 Hom.: 17

Bravo AF: 0.00752

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00245 AC: 297

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.027	D
Polyphen		0.94	P
Vest4		0.65
MVP		0.71
MPC		1.1
ClinPred		0.065	T
GERP RS		5.0
Varity_R		0.58
gMVP		0.81
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs114521946; hg19: chr17-14063251; COSMIC: COSV55403245;