1-226984123-A-G

Position:

• 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).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: COQ8A NM_020247.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 2.95

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]

ACMG classification

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	c.1286A>G	p.Tyr429Cys	missense_variant	11/15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ8A	ENST00000366777.4	c.1286A>G	p.Tyr429Cys	missense_variant	11/15	1	NM_020247.5	ENSP00000355739	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152014 Hom.: 0 Cov.: 33

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: 78 AN: 250510 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135712

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.: 1 Cov.: 38 AF XY: 0.000292 AC XY: 212 AN XY: 727066

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: 37 AN: 152014 Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24 AN XY: 74228

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.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000371 AC: 45

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive ataxia due to ubiquinone deficiency Uncertain:3

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]. -
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	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Uncertain:2 Benign: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	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	Apr 07, 2022	- -

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	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.66	.;T;T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
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	T
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

Other links and lift over

dbSNP: rs144147839; hg19: chr1-227171824;