rs41303129

chr1-226982947-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020247.5(COQ8A):c.993C>T(p.Phe331=) 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 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 criteria provided, multiple submitters, no conflicts P:1 B:15 O:1
• Conservation: PhyloP100: -1.51

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 -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]. Clinvar id is 3645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226982947-C-T is described in Lovd as [Likely_benign]. Variant chr1-226982947-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ8A	NM_020247.5	c.993C>T	p.Phe331=	synonymous_variant	8/15	ENST00000366777.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ8A	ENST00000366777.4	c.993C>T	p.Phe331=	synonymous_variant	8/15	1	NM_020247.5	P1
COQ8A	ENST00000366778.5	c.837C>T	p.Phe279=	synonymous_variant	8/15	1
COQ8A	ENST00000485462.5	n.383C>T		non_coding_transcript_exon_variant	4/11	1
COQ8A	ENST00000478406.5	n.972C>T		non_coding_transcript_exon_variant	4/8	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

GnomAD3 exomes AF: 0.0157 AC: 3768 AN: 240686 Hom.: 53 AF XY: 0.0161 AC XY: 2118 AN XY: 131296

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 SAS exome AF: 0.0104

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

Gnomad4 AFR exome AF: 0.00270

Gnomad4 AMR exome AF: 0.00716

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.0254

Gnomad4 NFE exome AF: 0.0216

Gnomad4 OTH exome AF: 0.0177

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

Gnomad4 AFR AF: 0.00377

Gnomad4 AMR AF: 0.00692

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0189 Hom.: 12

Bravo AF: 0.0126

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:1 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency in ExAC 2.8% in european population with (24 homozygotes). Also Benign in Clinvar (by GeneDx and Emory) -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 12, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	This variant is associated with the following publications: (PMID: 26764160, 27884173, 27535533, 18319074, 32337771) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	COQ8A: BP4, BP7, BS1, BS2 -

Joubert syndrome 17 Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The c.993C>T (p.Phe331=) variant in ADCK3 has been identified in a French and Algerian individual with ubiquinone deficiency with cerebellar ataxia (PMID: 18319074), but has also been identified in >4% of European (Finnish) chromosomes and 33 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the c.993C>T variant may not impact protein function (PMID: 18319074). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive ubiquinone deficiency with cerebellar ataxia. -

Coenzyme Q10 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	0.21
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs41303129; hg19: chr1-227170648; COSMIC: COSV64658592; COSMIC: COSV64658592;