rs144147839

Positions:

chr1-226984123-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020247.5(COQ8A):c.1286A>G(p.Tyr429Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,613,492 control chromosomes in the GnomAD database, including 1 homozygotes. 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. Y429H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 2.95

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 links:

ENSG00000288674 (HGNC:):

ENSG00000288674 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ8A	NM_020247.5 linkuse as main transcript	c.1286A>G	p.Tyr429Cys	missense_variant	11/15	ENST00000366777.4	NP_064632.2	Q8NI60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COQ8A	ENST00000366777.4 linkuse as main transcript	c.1286A>G	p.Tyr429Cys	missense_variant	11/15	1	NM_020247.5	ENSP00000355739.3	Q8NI60-1
ENSG00000288674	ENST00000366779.6 linkuse as main transcript	n.*6013A>G		non_coding_transcript_exon_variant	28/32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6 linkuse as main transcript	n.*6013A>G		3_prime_UTR_variant	28/32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000311

AC:

AN:

250510

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000601

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000259

AC:

379

AN:

1461478

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

212

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.000299

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000243

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000479

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000371

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 06, 2024	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2016	The Y429C missense mutation in the ADCK3 gene has been reported previously in association with adult-onset cerebellar ataxia according to the Human Gene Mutation Database (Hovarth et al., 2012). -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function. -

Autosomal recessive ataxia due to ubiquinone deficiency

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 09, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 10, 2024

Variant summary: COQ8A c.1286A>G (p.Tyr429Cys) results in a non-conservative amino acid change in the ABC1 atypical kinase-like domain (IPR004147) of the coded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 250510 control chromosomes. c.1286A>G has been reported in the literature in two siblings affected with Autosomal Recessive Adult-onset cerebellar ataxia, without second reportable variant (Horvath_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Ataxia Due To Ubiquinone Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22036850). ClinVar contains an entry for this variant (Variation ID: 214044). Based on the evidence outlined above, the variant was classified as uncertain significance. -

COQ8A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2024

The COQ8A c.1286A>G variant is predicted to result in the amino acid substitution p.Tyr429Cys. This variant was reported without a second variant in COQ8A in an individual with adult-onset cerebellar ataxia (Horvath et al 2012. PubMed ID: 22036850). This variant is reported in 0.061% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.46

T;.;T

Eigen

Benign

-0.012

Eigen_PC

Benign

0.058

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.66

.;T;T

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.90

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Benign

0.18

Sift

Benign

0.067

T;T;T

Sift4G

Uncertain

0.051

T;D;T

Polyphen

0.10

B;.;B

Vest4

0.83

MVP

0.69

MPC

0.088

ClinPred

0.073

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.48

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over