rs121908985
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002495.4(NDUFS4):c.291del(p.Trp97Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
NDUFS4
NM_002495.4 frameshift
NM_002495.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.59
Genes affected
NDUFS4 (HGNC:7711): (NADH:ubiquinone oxidoreductase subunit S4) This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]
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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 5-53646344-TG-T is Pathogenic according to our data. Variant chr5-53646344-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 6888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53646344-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFS4 | NM_002495.4 | c.291del | p.Trp97Ter | frameshift_variant | 3/5 | ENST00000296684.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFS4 | ENST00000296684.10 | c.291del | p.Trp97Ter | frameshift_variant | 3/5 | 1 | NM_002495.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461654Hom.: 0 Cov.: 44 AF XY: 0.00000825 AC XY: 6AN XY: 727134
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GnomAD4 genome ? Cov.: 32
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2016 | The c.291delG variant in the NDUFS4 gene has been reported previously in several unrelated individuals with patients with mitochondrial complex I deficiency or Leigh disease who were homozygous for c.291delG or compound heterozygous for c.291delG and another pathogenic variant in the NDUFS4 gene (Budde et al., 2000; Assouline et al., 2012; Ortigoza-Escobar et al., 2016). This variant is reported to be a founder mutation in the North African population (Assouline et al., 2012). The deletion changes the Tryptophan codon at position 97 to a Stop codon, denoted W97X. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.291delG to be a pathogenic variant. - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Trp97*) in the NDUFS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFS4 are known to be pathogenic (PMID: 10944442, 16213125). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 10944442, 27079373). ClinVar contains an entry for this variant (Variation ID: 6888). For these reasons, this variant has been classified as Pathogenic. - |
Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 18, 2000 | - - |
Leigh syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2022 | Variant summary: NDUFS4 c.291delG (p.Trp97X) 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 have been classified as pathogenic by our laboratory. The variant was absent in 251386 control chromosomes. c.291delG has been reported in the literature in multiple individuals affected with Leigh Syndrome (Assouline_2012, Jou_2019, Budde_2000). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
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