rs76249490

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020247.5(COQ8A):c.238C>T(p.His80Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,614,012 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H80H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 78 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.75

Publications

9 publications found

Variant links:

Genes affected

COQ8A (HGNC:16812): (coenzyme Q8A) This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

COQ8A Gene-Disease associations (from GenCC):

autosomal recessive ataxia due to ubiquinone deficiency
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
coenzyme Q10 deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

COQ8A links:

ENSG00000288674 (HGNC:):

ENSG00000288674 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029934943).

BP6

Variant 1-226965060-C-T is Benign according to our data. Variant chr1-226965060-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 214026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00248 (378/152358) while in subpopulation EAS AF = 0.0465 (241/5180). AF 95% confidence interval is 0.0417. There are 9 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ8A	NM_020247.5 link	c.238C>T	p.His80Tyr	missense_variant	Exon 3 of 15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COQ8A	ENST00000366777.4 link	c.238C>T	p.His80Tyr	missense_variant	Exon 3 of 15	1	NM_020247.5	ENSP00000355739.3
ENSG00000288674	ENST00000366779.6 link	n.*4965C>T		non_coding_transcript_exon_variant	Exon 20 of 32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6 link	n.*4965C>T		3_prime_UTR_variant	Exon 20 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

379

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0466

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00661

AC:

1660

AN:

251282

AF XY:

0.00687

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.0529

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00233

AC:

3410

AN:

1461654

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

2013

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000880

AC:

AN:

26136

East Asian (EAS)

AF:

0.0360

AC:

1428

AN:

39700

South Asian (SAS)

AF:

0.0189

AC:

1628

AN:

86258

European-Finnish (FIN)

AF:

0.0000752

AC:

AN:

53190

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1112010

Other (OTH)

AF:

0.00402

AC:

243

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

233

465

698

930

1163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00248

AC:

378

AN:

152358

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

226

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41584

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0465

AC:

241

AN:

5180

South Asian (SAS)

AF:

0.0207

AC:

100

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00197

Hom.:

Bravo

AF:

0.00238

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00640

AC:

777

Asia WGS

AF:

0.0330

AC:

115

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COQ8A: BP4, BS1, BS2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Dec 03, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jun 25, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive ataxia due to ubiquinone deficiency

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jan 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive cerebellar ataxia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.096

T;.;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.0

.;T;T

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

1.8

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.79

N;N;N

REVEL

Benign

0.085

Sift

Benign

0.035

D;D;D

Sift4G

Uncertain

0.037

D;D;D

Vest4

0.096

ClinPred

0.015

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.20

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over