chr12-94971477-ATCT-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_SupportingBS1_SupportingBS2
The NM_018838.5(NDUFA12):c.398_400delAGA(p.Lys133del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00146 in 1,614,170 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 4 hom. )
Consequence
NDUFA12
NM_018838.5 disruptive_inframe_deletion
NM_018838.5 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.07
Genes affected
NDUFA12 (HGNC:23987): (NADH:ubiquinone oxidoreductase subunit A12) This gene encodes a protein which is part of mitochondrial complex 1, part of the oxidative phosphorylation system in mitochondria. Complex 1 transfers electrons to ubiquinone from NADH which establishes a proton gradient for the generation of ATP. Mutations in this gene are associated with Leigh syndrome due to mitochondrial complex 1 deficiency. Pseudogenes of this gene are located on chromosomes 5 and 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_018838.5. Strenght limited to Supporting due to length of the change: 1aa.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.001 (153/152304) while in subpopulation NFE AF= 0.00196 (133/68024). AF 95% confidence interval is 0.00168. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes 0.00101 AC: 153AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000808 AC: 203AN: 251354Hom.: 0 AF XY: 0.000861 AC XY: 117AN XY: 135846
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GnomAD4 exome AF: 0.00150 AC: 2200AN: 1461866Hom.: 4 AF XY: 0.00148 AC XY: 1075AN XY: 727238
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GnomAD4 genome 0.00100 AC: 153AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2025 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 29, 2024 | This variant, c.398_400del, results in the deletion of 1 amino acid(s) of the NDUFA12 protein (p.Lys133del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs561604238, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NDUFA12-related conditions. ClinVar contains an entry for this variant (Variation ID: 806925). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2016 | - - |
Inborn genetic diseases Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at