rs140246430
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_020247.5(COQ8A):c.901C>T(p.Arg301Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
COQ8A
NM_020247.5 missense
NM_020247.5 missense
Scores
9
5
4
Clinical Significance
Conservation
PhyloP100: 0.717
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.903
PP5
Variant 1-226982725-C-T is Pathogenic according to our data. Variant chr1-226982725-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 434087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COQ8A | NM_020247.5 | c.901C>T | p.Arg301Trp | missense_variant | 7/15 | ENST00000366777.4 | NP_064632.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COQ8A | ENST00000366777.4 | c.901C>T | p.Arg301Trp | missense_variant | 7/15 | 1 | NM_020247.5 | ENSP00000355739 | P1 | |
COQ8A | ENST00000366778.5 | c.745C>T | p.Arg249Trp | missense_variant | 7/15 | 1 | ENSP00000355740 | |||
COQ8A | ENST00000485462.5 | n.291C>T | non_coding_transcript_exon_variant | 3/11 | 1 | |||||
COQ8A | ENST00000478406.5 | n.880C>T | non_coding_transcript_exon_variant | 3/8 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250778Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135786
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461352Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17AN XY: 726974
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74362
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 15, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 29, 2022 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 17, 2022 | The c.901C>T (p.R301W) alteration is located in exon 7 (coding exon 6) of the COQ8A gene. This alteration results from a C to T substitution at nucleotide position 901, causing the arginine (R) at amino acid position 301 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (10/282150) total alleles studied. The highest observed frequency was 0.01% (8/128598) of European (non-Finnish) alleles. This variant has been detected in conjunction with a COQ8A pathogenic variant in multiple individuals with clinical features of COQ8-related conezyme Q10 deficiency (Galosi, 2019; Schirinzi, 2019). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2022 | This variant is present in population databases (rs140246430, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 301 of the COQ8A protein (p.Arg301Trp). This missense change has been observed in individual(s) with clinical features of primary coenzyme Q10 deficiency (PMID: 29915382, 30637285, 31890231, 32337771). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects COQ8A function (PMID: 32337771). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 434087). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Pathogenic
.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at