10-100526440-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005004.4(NDUFB8):c.427A>G(p.Met143Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,611,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000072 ( 0 hom. )
Consequence
NDUFB8
NM_005004.4 missense
NM_005004.4 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 7.67
Genes affected
NDUFB8 (HGNC:7703): (NADH:ubiquinone oxidoreductase subunit B8) Involved in mitochondrial respiratory chain complex I assembly. Located in endoplasmic reticulum and mitochondrion. Part of mitochondrial respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency 32. Biomarker of Alzheimer's disease and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFB8 | NM_005004.4 | c.427A>G | p.Met143Val | missense_variant | 4/5 | ENST00000299166.9 | |
NDUFB8 | NM_001284367.2 | c.427A>G | p.Met143Val | missense_variant | 4/5 | ||
NDUFB8 | NM_001284368.1 | c.334A>G | p.Met112Val | missense_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFB8 | ENST00000299166.9 | c.427A>G | p.Met143Val | missense_variant | 4/5 | 1 | NM_005004.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152072Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000602 AC: 15AN: 249274Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134872
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GnomAD4 exome AF: 0.0000719 AC: 105AN: 1459660Hom.: 0 Cov.: 30 AF XY: 0.0000620 AC XY: 45AN XY: 726216
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74266
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with NDUFB8-related conditions. This variant is present in population databases (rs765591575, gnomAD 0.02%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 143 of the NDUFB8 protein (p.Met143Val). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of catalytic residue at M143 (P = 0.0366);.;Gain of catalytic residue at M143 (P = 0.0366);
MVP
MPC
ClinPred
T
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