rs376462712

chr1-226977490-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020247.5(COQ8A):c.697G>A(p.Ala233Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000503 in 1,567,260 control chromosomes in the GnomAD database, including 12 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 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (12 hom.)
• Consequence: COQ8A NM_020247.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 7.19

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009729356).
• BP6: Variant 1-226977490-G-A is Benign according to our data. Variant chr1-226977490-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214033.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000269 (41/152288) while in subpopulation SAS AF= 0.00849 (41/4828). AF 95% confidence interval is 0.00643. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ8A	NM_020247.5	c.697G>A	p.Ala233Thr	missense_variant	5/15	ENST00000366777.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ8A	ENST00000366777.4	c.697G>A	p.Ala233Thr	missense_variant	5/15	1	NM_020247.5	P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00134 AC: 232 AN: 173048 Hom.: 6 AF XY: 0.00176 AC XY: 163 AN XY: 92382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00927

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000858

Gnomad OTH exome AF: 0.000862

GnomAD4 exome AF: 0.000529 AC: 748 AN: 1414972 Hom.: 12 Cov.: 31 AF XY: 0.000761 AC XY: 532 AN XY: 699320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00832

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.000477

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000837 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00111 AC: 126

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	COQ8A: BS1 -

Autosomal recessive cerebellar ataxia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	0.061
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.47	P;.;P
Vest4		0.66
MVP		0.87
MPC		0.053
ClinPred		0.071	T
GERP RS		4.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.9
Varity_R		0.16
gMVP		0.69

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: rs376462712; hg19: chr1-227165191; COSMIC: COSV64658296; COSMIC: COSV64658296;