rs772294726
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_174889.5(NDUFAF2):c.221G>A(p.Trp74Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,597,952 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
NDUFAF2
NM_174889.5 stop_gained
NM_174889.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.56
Genes affected
NDUFAF2 (HGNC:28086): (NADH:ubiquinone oxidoreductase complex assembly factor 2) NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.567 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 5-61098995-G-A is Pathogenic according to our data. Variant chr5-61098995-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFAF2 | NM_174889.5 | c.221G>A | p.Trp74Ter | stop_gained | 3/4 | ENST00000296597.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFAF2 | ENST00000296597.10 | c.221G>A | p.Trp74Ter | stop_gained | 3/4 | 1 | NM_174889.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151918Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248658Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134554
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GnomAD4 exome AF: 0.0000235 AC: 34AN: 1446034Hom.: 0 Cov.: 26 AF XY: 0.0000278 AC XY: 20AN XY: 719926
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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
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2022 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 96 amino acids are lost; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27861786, 20818383, 34234304) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Trp74*) in the NDUFAF2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 96 amino acid(s) of the NDUFAF2 protein. This variant is present in population databases (rs772294726, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of Leigh syndrome (PMID: 20818383, 34234304). ClinVar contains an entry for this variant (Variation ID: 496555). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NDUFAF2 function (PMID: 20818383). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Leigh syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2016 | Variant summary: The NDUFAF2 c.221G>A (p.Trp74X) variant results in a premature termination codon, predicted to cause a truncated or absent NDUFAF2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/120338 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic NDUFAF2 variant (0.00125). Additionally, this variant was identified in at least one Leigh Syndrome patient reported in the literature in homozygous state. Fibroblasts from this patient show that the variant results in occasional exon 3 skipping, but most notably, no detectable protein product (Calvo_Nat Genet_2010). Taken together, this variant is classified as pathogenic. - |
Mitochondrial complex 1 deficiency, nuclear type 10 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 17, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at