chr11-68033254-A-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_002496.4(NDUFS8):āc.343A>Gā(p.Lys115Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,609,414 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000048 ( 0 hom. )
Consequence
NDUFS8
NM_002496.4 missense
NM_002496.4 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 8.72
Genes affected
NDUFS8 (HGNC:7715): (NADH:ubiquinone oxidoreductase core subunit S8) This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process. Mutations in this gene have been associated with Leigh syndrome. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a domain 4Fe-4S ferredoxin-type 1 (size 29) in uniprot entity NDUS8_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002496.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.781
PP5
Variant 11-68033254-A-G is Pathogenic according to our data. Variant chr11-68033254-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216970.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFS8 | NM_002496.4 | c.343A>G | p.Lys115Glu | missense_variant | 5/7 | ENST00000313468.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFS8 | ENST00000313468.10 | c.343A>G | p.Lys115Glu | missense_variant | 5/7 | 1 | NM_002496.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000210 AC: 5AN: 238056Hom.: 0 AF XY: 0.0000231 AC XY: 3AN XY: 130082
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GnomAD4 exome AF: 0.00000480 AC: 7AN: 1457264Hom.: 0 Cov.: 34 AF XY: 0.00000552 AC XY: 4AN XY: 724814
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74330
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Leigh syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Oct 16, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 27, 2020 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 216970). This missense change has been observed in individual(s) with Leigh syndrome (PMID: 25326637). This variant is present in population databases (rs764276946, gnomAD 0.02%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 115 of the NDUFS8 protein (p.Lys115Glu). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;P;.
Vest4
MutPred
Loss of methylation at K115 (P = 0.0079);Loss of methylation at K115 (P = 0.0079);Loss of methylation at K115 (P = 0.0079);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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