rs121912638
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_002496.4(NDUFS8):c.305G>A(p.Arg102His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,611,892 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
NDUFS8
NM_002496.4 missense
NM_002496.4 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 9.38
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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002496.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.864
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFS8 | NM_002496.4 | c.305G>A | p.Arg102His | missense_variant | 5/7 | ENST00000313468.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFS8 | ENST00000313468.10 | c.305G>A | p.Arg102His | missense_variant | 5/7 | 1 | NM_002496.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000204 AC: 5AN: 244576Hom.: 0 AF XY: 0.00000751 AC XY: 1AN XY: 133086
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1459690Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13AN XY: 726106
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30055843, 9837812) - |
Mitochondrial complex 1 deficiency, nuclear type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1998 | - - |
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;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;D;.;.
Vest4
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