20-13816520-T-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_024120.5(NDUFAF5):āc.836T>Gā(p.Met279Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,000 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 (ā ā ).
Frequency
Consequence
NM_024120.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251314Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135828
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461808Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727214
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 16 Pathogenic:4
PM2_Supporting+PP3_Moderate+PM3+PP4 -
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Leigh syndrome Pathogenic:2
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Variant summary: NDUFAF5 c.836T>G (p.Met279Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251314 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NDUFAF5 causing Leigh Syndrome (5.6e-05 vs 0.00056), allowing no conclusion about variant significance. c.836T>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple well characterized and comprehensively sequenced (by WES) individuals of East Asian ancestry affected with heterogeneous phenotypes of mitochondrial complex 1 assembly gene deficiency such as Leigh Syndrome, neurodevelopmental delay accompanied by unexplained dyspnea, lactic acidosis and Bilateral striatal necrosis (BSN) (example, Farwell_2015, Tong_2018, Simon_2019, Bi_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely Pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Inborn genetic diseases Pathogenic:1
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not provided Pathogenic:1
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 279 of the NDUFAF5 protein (p.Met279Arg). This variant is present in population databases (rs761389904, gnomAD 0.09%). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 29581464, 30473481, 30581749, 34177781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225036). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDUFAF5 protein function. For these reasons, this variant has been classified as Pathogenic. -
Mitochondrial complex I deficiency Uncertain:1
Likely pathogenicity based on finding it once in our laboratory homozygous in a 13-year-old female with regression of motor skills, minor cognitive delays, hypotonia, restrictive lung disease, epilepsy, short stature, structural brain abnormalities, esotropia, hypertension -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at