11-68033140-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_002496.4(NDUFS8):c.229C>T(p.Arg77Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,682 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
Consequence
NM_002496.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152134Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000404 AC: 10AN: 247810Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134652
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460548Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 726608
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152134Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
ClinVar
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 2 Pathogenic:1Uncertain:1
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not provided Uncertain:1
The R77W variant in the NDUFS8 gene has previously been reported in an individual with isolated complex I deficiency, who also harbors a second variant in this gene. Complex I activity was significantly decreased in both the muscle and fibroblasts of this individual (Haack et al., 2012). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R77W 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 conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, we interpret R77W as a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at