rs76249490

Positions:

• chr1-226965060-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.75

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 214026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226965060-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ8A	NM_020247.5	c.238C>T	p.His80Tyr	missense_variant	3/15	ENST00000366777.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ8A	ENST00000366777.4	c.238C>T	p.His80Tyr	missense_variant	3/15	1	NM_020247.5	P1
COQ8A	ENST00000366778.5	c.82C>T	p.His28Tyr	missense_variant	3/15	1
COQ8A	ENST00000489044.1	n.449C>T		non_coding_transcript_exon_variant	3/5	3
COQ8A	ENST00000478406.5	n.107-12389C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152240 Hom.: 9 Cov.: 33

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

GnomAD3 exomes AF: 0.00661 AC: 1660 AN: 251282 Hom.: 44 AF XY: 0.00687 AC XY: 933 AN XY: 135884

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 SAS exome AF: 0.0206

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.: 78 Cov.: 32 AF XY: 0.00277 AC XY: 2013 AN XY: 727126

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.0360

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152358 Hom.: 9 Cov.: 33 AF XY: 0.00303 AC XY: 226 AN XY: 74504

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0465

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00204 Hom.: 13

Bravo AF: 0.00238

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2014	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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Autosomal recessive ataxia due to ubiquinone deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Autosomal recessive cerebellar ataxia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.096	T;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.45	.;T;T
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Benign	0.42	T
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
Polyphen		0.23	B;.;B
Vest4		0.096
MVP		0.57
MPC		0.049
ClinPred		0.015	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.20

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: rs76249490; hg19: chr1-227152761; COSMIC: COSV64656787;