rs267606913
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_004553.6(NDUFS6):c.344G>A(p.Cys115Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C115R) has been classified as Pathogenic.
Frequency
Consequence
NM_004553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFS6 | NM_004553.6 | c.344G>A | p.Cys115Tyr | missense_variant | 4/4 | ENST00000274137.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFS6 | ENST00000274137.10 | c.344G>A | p.Cys115Tyr | missense_variant | 4/4 | 1 | NM_004553.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251408Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 9 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 11, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2009 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 15, 2023 | 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. This variant disrupts the p.Cys115 amino acid residue in NDUFS6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28429146, 30948790). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 6018). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 19259137). This variant is present in population databases (rs267606913, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 115 of the NDUFS6 protein (p.Cys115Tyr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at