rs759470563

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020247.5(COQ8A):ā€‹c.1097A>Gā€‹(p.Gln366Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000059 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

1
3
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.43
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2677288).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COQ8ANM_020247.5 linkuse as main transcriptc.1097A>G p.Gln366Arg missense_variant 9/15 ENST00000366777.4 NP_064632.2 Q8NI60-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COQ8AENST00000366777.4 linkuse as main transcriptc.1097A>G p.Gln366Arg missense_variant 9/151 NM_020247.5 ENSP00000355739.3 Q8NI60-1
ENSG00000288674ENST00000366779.6 linkuse as main transcriptn.*5824A>G non_coding_transcript_exon_variant 26/322 ENSP00000355741.2
ENSG00000288674ENST00000366779.6 linkuse as main transcriptn.*5824A>G 3_prime_UTR_variant 26/322 ENSP00000355741.2

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251250
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461592
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.00
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:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 21, 2022This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 366 of the COQ8A protein (p.Gln366Arg). This variant is present in population databases (rs759470563, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with COQ8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 585373). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COQ8A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 16, 2022In 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 -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsNov 21, 2017- -
Autosomal recessive ataxia due to ubiquinone deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJul 09, 2020This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T;.;T
Eigen
Benign
-0.052
Eigen_PC
Benign
0.15
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
.;D;D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.27
T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-2.1
N;N;N
REVEL
Benign
0.19
Sift
Benign
0.067
T;T;T
Sift4G
Benign
0.12
T;T;T
Polyphen
0.15
B;.;B
Vest4
0.44
MutPred
0.40
Gain of MoRF binding (P = 0.0159);.;Gain of MoRF binding (P = 0.0159);
MVP
0.62
MPC
0.058
ClinPred
0.25
T
GERP RS
5.4
Varity_R
0.60
gMVP
0.57

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.

Other links and lift over

dbSNP: rs759470563; hg19: chr1-227171269; API