rs762093523
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_152416.4(NDUFAF6):c.485del(p.Asn162IlefsTer27) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
NDUFAF6
NM_152416.4 frameshift, splice_region
NM_152416.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.14
Genes affected
NDUFAF6 (HGNC:28625): (NADH:ubiquinone oxidoreductase complex assembly factor 6) This gene encodes a protein that localizes to mitochondria and contains a predicted phytoene synthase domain. The encoded protein plays an important role in the assembly of complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain through regulation of subunit ND1 biogenesis. Mutations in this gene are associated with complex I enzymatic deficiency. [provided by RefSeq, Nov 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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
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Variant 8-95045545-GA-G is Pathogenic according to our data. Variant chr8-95045545-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1064697.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFAF6 | NM_152416.4 | c.485del | p.Asn162IlefsTer27 | frameshift_variant, splice_region_variant | 5/9 | ENST00000396124.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFAF6 | ENST00000396124.9 | c.485del | p.Asn162IlefsTer27 | frameshift_variant, splice_region_variant | 5/9 | 2 | NM_152416.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248968Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135086
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GnomAD4 exome AF: 0.00000549 AC: 8AN: 1458384Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4AN XY: 725762
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74230
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 17 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Istanbul Faculty of Medicine, Istanbul University | Dec 25, 2020 | Affected patient is compound heterozygous with c.420+784C>T in trans allele - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2023 | Frameshift 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; Identified in trans with an intronic variant in an individual with suspected mitochondrial disease with symptoms including regression, dystonia and abnormal MRI (PMID: 37377599); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37377599) - |
Computational scores
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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