rs150243147

Positions:

chr1-226982943-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_020247.5(COQ8A):c.989A>G(p.Tyr330Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,610,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.00300

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_020247.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018922746).

BP6

Variant 1-226982943-A-G is Benign according to our data. Variant chr1-226982943-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235765.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00115 (175/152354) while in subpopulation AFR AF= 0.00406 (169/41588). AF 95% confidence interval is 0.00356. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ8A	NM_020247.5 linkuse as main transcript	c.989A>G	p.Tyr330Cys	missense_variant	8/15	ENST00000366777.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ8A	ENST00000366777.4 linkuse as main transcript	c.989A>G	p.Tyr330Cys	missense_variant	8/15	1	NM_020247.5	P1	Q8NI60-1
COQ8A	ENST00000366778.5 linkuse as main transcript	c.833A>G	p.Tyr278Cys	missense_variant	8/15	1			Q8NI60-3
COQ8A	ENST00000485462.5 linkuse as main transcript	n.379A>G		non_coding_transcript_exon_variant	4/11	1
COQ8A	ENST00000478406.5 linkuse as main transcript	n.968A>G		non_coding_transcript_exon_variant	4/8	2

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

175

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000275

AC:

AN:

243722

Hom.:

AF XY:

0.000233

AC XY:

AN XY:

132828

show subpopulations

Gnomad AFR exome

AF:

0.00370

Gnomad AMR exome

AF:

0.000234

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

179

AN:

1458592

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

725536

show subpopulations

Gnomad4 AFR exome

AF:

0.00440

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152354

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00406

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000321

Hom.:

Bravo

AF:

0.00151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000339

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	COQ8A: BS1 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 09, 2020

- -

COQ8A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;.;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.31

M_CAP

Benign

0.043

MetaRNN

Benign

0.019

T;T;T

MetaSVM

Benign

-0.87

MutationTaster

Benign

0.68

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.013

B;.;B

Vest4

0.63

MVP

0.60

MPC

0.055

ClinPred

0.024

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.46

gMVP

0.58

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

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