8-96231067-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_006294.5(UQCRB):c.324G>T(p.Trp108Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 1 hom. )
Consequence
UQCRB
NM_006294.5 missense
NM_006294.5 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 6.49
Genes affected
UQCRB (HGNC:12582): (ubiquinol-cytochrome c reductase binding protein) This gene encodes a subunit of the ubiquinol-cytochrome c oxidoreductase complex, which consists of one mitochondrial-encoded and 10 nuclear-encoded subunits. The protein encoded by this gene binds ubiquinone and participates in the transfer of electrons when ubiquinone is bound. This protein plays an important role in hypoxia-induced angiogenesis through mitochondrial reactive oxygen species-mediated signaling. Mutations in this gene are associated with mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. Related pseudogenes have been identified on chromosomes 1, 5 and X. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.821
PP5
Variant 8-96231067-C-A is Pathogenic according to our data. Variant chr8-96231067-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215347.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UQCRB | NM_006294.5 | c.324G>T | p.Trp108Cys | missense_variant | 4/4 | ENST00000287022.10 | |
UQCRB | NM_001199975.3 | c.228G>T | p.Trp76Cys | missense_variant | 5/5 | ||
UQCRB | NM_001254752.2 | c.*38G>T | 3_prime_UTR_variant | 5/5 | |||
UQCRB | NR_045639.2 | n.629G>T | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UQCRB | ENST00000287022.10 | c.324G>T | p.Trp108Cys | missense_variant | 4/4 | 1 | NM_006294.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152164Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461118Hom.: 1 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 726868
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2014 | p.Trp108Cys (TGG>TGT): c.324 G>T in exon 4 of the UQCRB gene (NM_006294.3). The W108C likely pathogenic variant identified in the UQCRB gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The W108C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2023 | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 108 of the UQCRB protein (p.Trp108Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UQCRB-related conditions. ClinVar contains an entry for this variant (Variation ID: 215347). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D;D
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 7e-04);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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