rs765791496
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_016035.5(COQ4):c.144G>T(p.Gln48His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,459,730 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
COQ4
NM_016035.5 missense
NM_016035.5 missense
Scores
4
12
3
Clinical Significance
Conservation
PhyloP100: 2.60
Genes affected
COQ4 (HGNC:19693): (coenzyme Q4) This gene encodes a component of the coenzyme Q biosynthesis pathway. Coenzyme Q, an essential component of the electron transport chain, shuttles electrons between complexes I or II to complex III of the mitochondrial transport chain. This protein appears to play a structural role in stabilizing a complex that contains most of the coenzyme Q biosynthesis enzymes. Mutations in this gene are associated with mitochondrial disorders linked to coenzyme Q deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a chain Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (size 234) in uniprot entity COQ4_HUMAN there are 48 pathogenic changes around while only 10 benign (83%) in NM_016035.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.862
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COQ4 | NM_016035.5 | c.144G>T | p.Gln48His | missense_variant | 2/7 | ENST00000300452.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COQ4 | ENST00000300452.8 | c.144G>T | p.Gln48His | missense_variant | 2/7 | 1 | NM_016035.5 | P1 | |
COQ4 | ENST00000372875.3 | c.144G>T | p.Gln48His | missense_variant | 2/4 | 2 | |||
COQ4 | ENST00000608951.5 | c.144G>T | p.Gln48His | missense_variant | 2/3 | 2 | |||
COQ4 | ENST00000609948.1 | c.144G>T | p.Gln48His | missense_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000167 AC: 4AN: 239160Hom.: 0 AF XY: 0.0000305 AC XY: 4AN XY: 131288
GnomAD3 exomes
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GnomAD4 exome AF: 0.0000445 AC: 65AN: 1459730Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37AN XY: 726230
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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Cov.:
33
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3
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2018 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with COQ4-related disease. This variant is present in population databases (rs765791496, ExAC 0.002%). This sequence change replaces glutamine with histidine at codon 48 of the COQ4 protein (p.Gln48His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;.;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;.;D
Vest4
MutPred
Loss of catalytic residue at Q48 (P = 0.0071);Loss of catalytic residue at Q48 (P = 0.0071);Loss of catalytic residue at Q48 (P = 0.0071);Loss of catalytic residue at Q48 (P = 0.0071);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at