1-226982996-C-T

Variant names:

• chr1-226982996-C-T
• rs771578775
• NM_020247.5:c.1042C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020247.5(COQ8A):​c.1042C>T​(p.Arg348*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,598,866 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: COQ8A NM_020247.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 2.58
• Publications: 11 publications found

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]

COQ8A Gene-Disease associations (from GenCC):

• autosomal recessive ataxia due to ubiquinone deficiency

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• coenzyme Q10 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

ENSG00000288674 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-226982996-C-T is Pathogenic according to our data. Variant chr1-226982996-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 242458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020247.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ8A	NM_020247.5	MANE Select	c.1042C>T	p.Arg348*	stop_gained	Exon 8 of 15	NP_064632.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ8A	ENST00000366777.4	TSL:1 MANE Select	c.1042C>T	p.Arg348*	stop_gained	Exon 8 of 15	ENSP00000355739.3
	COQ8A	ENST00000366778.5	TSL:1	c.886C>T	p.Arg296*	stop_gained	Exon 8 of 15	ENSP00000355740.1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.*5769C>T		non_coding_transcript_exon	Exon 25 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152220 Hom.: 0 Cov.: 34

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000453 AC: 10 AN: 220860 AF XY: 0.0000415

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000943

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000718

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000353 AC: 51 AN: 1446646 Hom.: 0 Cov.: 34 AF XY: 0.0000390 AC XY: 28 AN XY: 718652

African (AFR) AF: 0.00 AC: 0 AN: 33072

American (AMR) AF: 0.0000937 AC: 4 AN: 42708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38644

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.0000398 AC: 44 AN: 1105514

Other (OTH) AF: 0.0000167 AC: 1 AN: 59780

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152220 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000669 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
4	-	-	Autosomal recessive ataxia due to ubiquinone deficiency (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		2.6
Vest4		0.90
GERP RS		5.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs771578775; hg19: chr1-227170697; COSMIC: COSV64657577; COSMIC: COSV64657577;