NM_020247.5:c.993C>T

Variant names:

• chr1-226982947-C-T
• rs41303129
• NM_020247.5:c.993C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020247.5(COQ8A):​c.993C>T​(p.Phe331Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,609,616 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (28 hom., cov: 33)
  • Exomes 𝑓: 0.019 (333 hom.)
• Consequence: COQ8A NM_020247.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:17 O:1
• Conservation: PhyloP100: -1.51
• Publications: 16 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-226982947-C-T is Benign according to our data. Variant chr1-226982947-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0137 (2089/152348) while in subpopulation NFE AF = 0.0207 (1411/68036). AF 95% confidence interval is 0.0198. There are 28 homozygotes in GnomAd4. There are 1003 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

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.993C>T	p.Phe331Phe	synonymous	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.993C>T	p.Phe331Phe	synonymous	Exon 8 of 15	ENSP00000355739.3	Q8NI60-1
	COQ8A	ENST00000366778.5	TSL:1	c.837C>T	p.Phe279Phe	synonymous	Exon 8 of 15	ENSP00000355740.1	Q8NI60-3
	ENSG00000288674	ENST00000366779.6	TSL:2	n.*5720C>T		non_coding_transcript_exon	Exon 25 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2088 AN: 152228 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0157 AC: 3768 AN: 240686 AF XY: 0.0161

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0245

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0195 AC: 28359 AN: 1457268 Hom.: 333 Cov.: 34 AF XY: 0.0192 AC XY: 13909 AN XY: 724730

African (AFR) AF: 0.00270 AC: 90 AN: 33380

American (AMR) AF: 0.00716 AC: 318 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 548 AN: 26082

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39448

South Asian (SAS) AF: 0.0110 AC: 946 AN: 85922

European-Finnish (FIN) AF: 0.0254 AC: 1315 AN: 51688

Middle Eastern (MID) AF: 0.0154 AC: 88 AN: 5716

European-Non Finnish (NFE) AF: 0.0216 AC: 23986 AN: 1110448

Other (OTH) AF: 0.0177 AC: 1065 AN: 60182

GnomAD4 genome AF: 0.0137 AC: 2089 AN: 152348 Hom.: 28 Cov.: 33 AF XY: 0.0135 AC XY: 1003 AN XY: 74496

African (AFR) AF: 0.00377 AC: 157 AN: 41600

American (AMR) AF: 0.00692 AC: 106 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4832

European-Finnish (FIN) AF: 0.0248 AC: 264 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0207 AC: 1411 AN: 68036

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0189 Hom.: 54

Bravo AF: 0.0126

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	6	not specified (6)
1	-	3	Autosomal recessive ataxia due to ubiquinone deficiency (5)
-	-	1	Coenzyme Q10 deficiency (1)
-	-	1	Joubert syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.21
DANN	Benign	0.81
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41303129; hg19: chr1-227170648; COSMIC: COSV64658592; COSMIC: COSV64658592;