rs387906299

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_020247.5(COQ8A):c.1750_1752delACC(p.Thr584del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000791 in 1,605,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T584T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

COQ8A
NM_020247.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 9.32

Publications

13 publications found

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 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

COQ8A links:

ENSG00000288674 (HGNC:):

ENSG00000288674 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_020247.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 1-226986538-GCAC-G is Pathogenic according to our data. Variant chr1-226986538-GCAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ8A	NM_020247.5 link	c.1750_1752delACC	p.Thr584del	conservative_inframe_deletion	Exon 15 of 15	ENST00000366777.4	NP_064632.2	Q8NI60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COQ8A	ENST00000366777.4 link	c.1750_1752delACC	p.Thr584del	conservative_inframe_deletion	Exon 15 of 15	1	NM_020247.5	ENSP00000355739.3	Q8NI60-1
ENSG00000288674	ENST00000366779.6 link	n.6477_6479delACC		non_coding_transcript_exon_variant	Exon 32 of 32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6 link	n.6477_6479delACC		3_prime_UTR_variant	Exon 32 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes

AF:

0.0000974

AC:

AN:

143788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000685

Gnomad ASJ

AF:

0.00216

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000772

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000123

AC:

AN:

251330

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461732

Hom.:

AF XY:

0.0000798

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00272

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111970

Other (OTH)

AF:

0.000149

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000974

AC:

AN:

143788

Hom.:

Cov.:

AF XY:

0.0000712

AC XY:

AN XY:

70226

show subpopulations

African (AFR)

AF:

0.0000258

AC:

AN:

38744

American (AMR)

AF:

0.0000685

AC:

AN:

14596

Ashkenazi Jewish (ASJ)

AF:

0.00216

AC:

AN:

3238

East Asian (EAS)

AF:

0.00

AC:

AN:

4834

South Asian (SAS)

AF:

0.00

AC:

AN:

4256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000772

AC:

AN:

64798

Other (OTH)

AF:

0.00

AC:

AN:

1946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000473

Hom.:

Bravo

AF:

0.0000907

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive ataxia due to ubiquinone deficiency

Pathogenic:5Other:1

Dec 17, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 22, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 18, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 31, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:3

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1750_1752del, results in the deletion of 1 amino acid(s) of the COQ8A protein (p.Thr584del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with CoQ10 deficiency (PMID: 18319074, 27572814, 29915382, 30637285). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects COQ8A function (PMID: 18319074, 26866375). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aug 18, 2021

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant may result in abnormal protein function. Studies showed this variant exhibited reduced protein function by failing to restore growth on selective respiratory medium (PMID: 18319074). This variant appears to segregate with disease in at least one family. -

Dec 04, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22359546, 24048965, 27106809, 24218524, 31621627, 31589614, 32337771, 18319074, 20495179, 29431110, 29915382, 31078656, 31980526, 37476682, 27572814, 33677064, 30637285) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.3

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

Publications

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rs387906299

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over