rs119468006

Positions:

• chr1-226982111-G-A
• chr1-226982111-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_020247.5(COQ8A):​c.815G>A​(p.Gly272Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G272A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COQ8A NM_020247.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.85

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]

ENSG00000288674 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_020247.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-226982111-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3233375.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 1-226982111-G-A is Pathogenic according to our data. Variant chr1-226982111-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3639.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ8A	NM_020247.5	c.815G>A	p.Gly272Asp	missense_variant	6/15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ8A	ENST00000366777.4	c.815G>A	p.Gly272Asp	missense_variant	6/15	1	NM_020247.5	ENSP00000355739.3
ENSG00000288674	ENST00000366779.6	n.*5542G>A		non_coding_transcript_exon_variant	23/32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6	n.*5542G>A		3_prime_UTR_variant	23/32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724550

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.4	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.61		Loss of methylation at R271 (P = 0.041);.;Loss of methylation at R271 (P = 0.041);
MVP		0.98
MPC		0.34
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs119468006; hg19: chr1-227169812;