rs200818252

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBS1_Supporting

The NM_001303.4(COX10):c.1027T>C(p.Cys343Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,613,824 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

COX10
NM_001303.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 2.29

Publications

1 publications found

Variant links:

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

COX10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 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, 4 uncertain in NM_001303.4

BP4

Computational evidence support a benign effect (MetaRNN=0.029314071).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000381 (58/152210) while in subpopulation NFE AF = 0.000706 (48/68024). AF 95% confidence interval is 0.000547. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX10	NM_001303.4	MANE Select	c.1027T>C	p.Cys343Arg	missense	Exon 7 of 7	NP_001294.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COX10	ENST00000261643.8	TSL:1 MANE Select	c.1027T>C	p.Cys343Arg	missense	Exon 7 of 7	ENSP00000261643.3
COX10	ENST00000580561.1	TSL:2	n.*516T>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000462190.1
COX10	ENST00000581931.5	TSL:2	n.*395T>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000462512.1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000289

AC:

AN:

249536

AF XY:

0.000304

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000623

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000549

AC:

802

AN:

1461614

Hom.:

Cov.:

AF XY:

0.000490

AC XY:

356

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000701

AC:

780

AN:

1111914

Other (OTH)

AF:

0.000265

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000381

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41472

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68024

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000459

Hom.:

Bravo

AF:

0.000359

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000296

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Leigh syndrome (2)

Mitochondrial complex IV deficiency, nuclear type 3 (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.32

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.79

M_CAP

Benign

0.020

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-3.0

PhyloP100

2.3

PrimateAI

Uncertain

0.69

PROVEAN

Benign

3.1

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

0.96

Polyphen

0.0

Vest4

0.15

MVP

0.082

MPC

0.44

ClinPred

0.17

GERP RS

2.6

Varity_R

0.20

gMVP

0.77

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over