1-226982947-C-T

Position:

chr1-226982947-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 28 hom., cov: 33)

Exomes 𝑓: 0.019 ( 333 hom. )

Consequence

COQ8A
NM_020247.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:16O:1

Conservation

PhyloP100: -1.51

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 [Likely_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 GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ8A	NM_020247.5 linkuse as main transcript	c.993C>T	p.Phe331=	synonymous_variant	8/15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ8A	ENST00000366777.4 linkuse as main transcript	c.993C>T	p.Phe331=	synonymous_variant	8/15	1	NM_020247.5	ENSP00000355739	P1	Q8NI60-1
COQ8A	ENST00000366778.5 linkuse as main transcript	c.837C>T	p.Phe279=	synonymous_variant	8/15	1		ENSP00000355740		Q8NI60-3
COQ8A	ENST00000485462.5 linkuse as main transcript	n.383C>T		non_coding_transcript_exon_variant	4/11	1
COQ8A	ENST00000478406.5 linkuse as main transcript	n.972C>T		non_coding_transcript_exon_variant	4/8	2

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2088

AN:

152228

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0161

AC XY:

2118

AN XY:

131296

show subpopulations

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.:

AF XY:

0.0192

AC XY:

13909

AN XY:

724730

show subpopulations

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.:

Cov.:

AF XY:

0.0135

AC XY:

1003

AN XY:

74496

show subpopulations

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.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COQ8A: BP4, BP7, BS1, BS2 -
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) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive ataxia due to ubiquinone deficiency

Pathogenic:1Benign:3Other:1

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

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 12, 2015	- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over