1-226961448-G-A

Position:

• chr1-226961448-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_020247.5(COQ8A):​c.63G>A​(p.Ala21=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,613,806 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 33)
  • Exomes 𝑓: 0.021 (384 hom.)
• Consequence: COQ8A NM_020247.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -2.29

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-226961448-G-A is Benign according to our data. Variant chr1-226961448-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136294.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}. Variant chr1-226961448-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0122 (1864/152370) while in subpopulation NFE AF= 0.0209 (1425/68030). AF 95% confidence interval is 0.02. There are 13 homozygotes in gnomad4. There are 811 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ8A	NM_020247.5	c.63G>A	p.Ala21=	synonymous_variant	2/15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ8A	ENST00000366777.4	c.63G>A	p.Ala21=	synonymous_variant	2/15	1	NM_020247.5	ENSP00000355739	P1
COQ8A	ENST00000366778.5	c.-34-60G>A		intron_variant		1		ENSP00000355740
COQ8A	ENST00000489044.1	n.274G>A		non_coding_transcript_exon_variant	2/5	3
COQ8A	ENST00000478406.5	n.107-16001G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1865 AN: 152252 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00778

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00649

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.0115 AC: 2894 AN: 251142 Hom.: 26 AF XY: 0.0112 AC XY: 1518 AN XY: 135830

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.00553

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00808

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0211 AC: 30865 AN: 1461436 Hom.: 384 Cov.: 31 AF XY: 0.0203 AC XY: 14758 AN XY: 727044

Gnomad4 AFR exome AF: 0.00355

Gnomad4 AMR exome AF: 0.00593

Gnomad4 ASJ exome AF: 0.00819

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00872

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.0194

GnomAD4 genome AF: 0.0122 AC: 1864 AN: 152370 Hom.: 13 Cov.: 33 AF XY: 0.0109 AC XY: 811 AN XY: 74514

Gnomad4 AFR AF: 0.00459

Gnomad4 AMR AF: 0.00777

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00649

Gnomad4 NFE AF: 0.0209

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0167 Hom.: 13

Bravo AF: 0.0121

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2013	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -

Autosomal recessive ataxia due to ubiquinone deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Coenzyme Q10 deficiency, Spinocerebellar Ataxia Type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs11549709; hg19: chr1-227149149;