5-60945256-A-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_174889.5(NDUFAF2):c.1A>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,642 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 Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
NDUFAF2
NM_174889.5 start_lost
NM_174889.5 start_lost
Scores
6
3
7
Clinical Significance
Conservation
PhyloP100: 3.10
Genes affected
NDUFAF2 (HGNC:28086): (NADH:ubiquinone oxidoreductase complex assembly factor 2) NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-60945256-A-T is Pathogenic according to our data. Variant chr5-60945256-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496596.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-60945256-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDUFAF2 | NM_174889.5 | c.1A>T | p.Met1? | start_lost | 1/4 | ENST00000296597.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDUFAF2 | ENST00000296597.10 | c.1A>T | p.Met1? | start_lost | 1/4 | 1 | NM_174889.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 249882Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135150
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460642Hom.: 0 Cov.: 67 AF XY: 0.00000138 AC XY: 1AN XY: 726558
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GnomAD4 genome ? Cov.: 32
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32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 29, 2023 | Disruption of the initiator codon has been observed in individuals with mitochondrial complex I deficiency (PMID: 18180188, 25590979). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the NDUFAF2 mRNA. The next in-frame methionine is located at codon 85. ClinVar contains an entry for this variant (Variation ID: 496596). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Mitochondrial complex 1 deficiency, nuclear type 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 13, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
B;.
Vest4
MutPred
Loss of disorder (P = 0.1622);Loss of disorder (P = 0.1622);
MVP
ClinPred
D
GERP RS
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