chr12-94971540-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_018838.5(NDUFA12):āc.338A>Gā(p.His113Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,250 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 (no stars).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Consequence
NDUFA12
NM_018838.5 missense
NM_018838.5 missense
Scores
10
5
4
Clinical Significance
Conservation
PhyloP100: 7.07
Genes affected
NDUFA12 (HGNC:23987): (NADH:ubiquinone oxidoreductase subunit A12) This gene encodes a protein which is part of mitochondrial complex 1, part of the oxidative phosphorylation system in mitochondria. Complex 1 transfers electrons to ubiquinone from NADH which establishes a proton gradient for the generation of ATP. Mutations in this gene are associated with Leigh syndrome due to mitochondrial complex 1 deficiency. Pseudogenes of this gene are located on chromosomes 5 and 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFA12 | NM_018838.5 | c.338A>G | p.His113Arg | missense_variant | 4/4 | ENST00000327772.7 | |
NDUFA12 | NM_001258338.2 | c.*58A>G | 3_prime_UTR_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFA12 | ENST00000327772.7 | c.338A>G | p.His113Arg | missense_variant | 4/4 | 1 | NM_018838.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251406Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135870
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GnomAD4 exome Cov.: 31
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74390
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0161);
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