rs71579253
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_005002.5(NDUFA9):c.253C>T(p.Arg85Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000408 in 1,613,792 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 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00042 ( 0 hom. )
Consequence
NDUFA9
NM_005002.5 missense
NM_005002.5 missense
Scores
15
2
2
Clinical Significance
Conservation
PhyloP100: 5.90
Genes affected
NDUFA9 (HGNC:7693): (NADH:ubiquinone oxidoreductase subunit A9) The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. A pseudogene has been identified on chromosome 12. [provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.932
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFA9 | NM_005002.5 | c.253C>T | p.Arg85Trp | missense_variant | 3/11 | ENST00000266544.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFA9 | ENST00000266544.10 | c.253C>T | p.Arg85Trp | missense_variant | 3/11 | 1 | NM_005002.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000269 AC: 41AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000263 AC: 66AN: 251112Hom.: 0 AF XY: 0.000273 AC XY: 37AN XY: 135706
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GnomAD4 exome AF: 0.000423 AC: 618AN: 1461528Hom.: 0 Cov.: 31 AF XY: 0.000419 AC XY: 305AN XY: 727072
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 85 of the NDUFA9 protein (p.Arg85Trp). This variant is present in population databases (rs71579253, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with NDUFA9-related conditions. ClinVar contains an entry for this variant (Variation ID: 214723). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 28, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 27, 2022 | The c.253C>T (p.R85W) alteration is located in exon 3 (coding exon 3) of the NDUFA9 gene. This alteration results from a C to T substitution at nucleotide position 253, causing the arginine (R) at amino acid position 85 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Leigh syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 23, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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