rs199754807
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_174889.5(NDUFAF2):āc.114C>Gā(p.Tyr38*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000116 in 1,614,102 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 Pathogenic (ā ā ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 33)
Exomes š: 0.00013 ( 0 hom. )
Consequence
NDUFAF2
NM_174889.5 stop_gained
NM_174889.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.86
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-60945369-C-G is Pathogenic according to our data. Variant chr5-60945369-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 419231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NDUFAF2 | NM_174889.5 | c.114C>G | p.Tyr38* | stop_gained | Exon 1 of 4 | ENST00000296597.10 | NP_777549.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251384Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135870
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GnomAD4 exome AF: 0.000126 AC: 184AN: 1461892Hom.: 0 Cov.: 37 AF XY: 0.000125 AC XY: 91AN XY: 727248
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GnomAD4 genome 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74358
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 10 Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 13, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 28, 2023 | The NDUFAF2 c.114C>G; p.Tyr38Ter variant (rs199754807) is reported in the literature in a homozygous individual affected with mitochondrial complex I deficiency (Hoefs 2009). This variant is reported in ClinVar (Variation ID: 419231) and is found in the general population with an overall allele frequency of 0.005% (15/282,774 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and while mRNA studies of patient cells suggest this variant may escape nonsense-mediated decay, it is predicted to result in a truncated protein. Patient cells homozygous for this variant exhibit significantly decreased mitochondrial complex I activity (Hoefs 2009). Based on available information, this variant is considered to be pathogenic. References: Hoefs SJ et al. Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency. Hum Mutat. 2009 Jul;30(7):E728-36. PMID: 19384974. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | A heterozygous nonsense variant, NM_174889.4(NDUFAF2):c.114C>G, has been identified in exon 1 of 4 of the NDUFAF2 gene. The variant is predicted to result in a premature stop codon at position 38 of the protein, NP_777549.1(NDUFAF2):p.(Tyr38*). This variant is predicted to result in loss of protein function through truncation (including the NDUFA12 domain), which is a reported mechanism of pathogenicity for this gene. The variant has been previously described as pathogenic and identified in a homozygous patient with complex I deficiency and clinical symptoms of Leigh disease (ClinVar, Hoefs, S. et al. (2009)). Additionally, functional studies showed a decrease in complex I activity in the cultured skin fibroblasts and a disturbance in the assembly of complex I (Hoefs, S. et al. (2009)). Other variants resulting in a truncated protein have been reported as pathogenic in this gene (ClinVar)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 18, 2024 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19384974) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 20, 2024 | This sequence change creates a premature translational stop signal (p.Tyr38*) in the NDUFAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFAF2 are known to be pathogenic (PMID: 18180188). This variant is present in population databases (rs199754807, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 19384974). ClinVar contains an entry for this variant (Variation ID: 419231). For these reasons, this variant has been classified as Pathogenic. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2018 | Variant summary: NDUFAF2 c.114C>G (p.Tyr38X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position has been classified as pathogenic by our laboratory (e.g. c.139C>T, p.Arg47X; c.221G>A, p.Trp74X). The variant allele was found at a frequency of 5.4e-05 in 277122 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFAF2 causing Leigh Syndrome (5.4e-05 vs 0.0013), allowing no conclusion about variant significance. The variant, c.114C>G, has been reported in the literature in one homozygote individual affected with Leigh Syndrome (Hoefs_2009). These data indicate that the variant may be associated with disease. The same publication reports experimental evidence showing no NDUFAF2 protein expression in patient's fibroblasts and a marked decrease in complex I activity (to 21-23% of the lowest control value). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 12, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 19384974] - |
NDUFAF2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 24, 2024 | The NDUFAF2 c.114C>G variant is predicted to result in premature protein termination (p.Tyr38*). This variant was reported in the homozygous state in an individual with mitochondrial complex I deficiency (Hoefs et al. 2009. PubMed ID: 19384974). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in NDUFAF2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cockayne syndrome type 1 Uncertain:1
| Uncertain significance, flagged submission | clinical testing | Counsyl | Apr 23, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
ClinPred
D
GERP RS
Splicing
Name
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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