rs387906425
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS1_ModeratePM2PP3
The ENST00000361567.2(MT-ND5):c.1394G>A(p.Gly465Glu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Mitomap GenBank:
Absent
Consequence
MT-ND5
ENST00000361567.2 missense
ENST00000361567.2 missense
Scores
Apogee2
Pathogenic
Clinical Significance
LHON
Conservation
PhyloP100: 9.29
Genes affected
MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PS1
?
Transcript ENST00000361567.2 (MT-ND5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
?
No frequency data in Mitomap. Probably very rare.
PP3
?
Apogee2 supports a deletorius effect, 0.95891684 >= 0.5 .
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-ND5 | ENST00000361567.2 | c.1394G>A | p.Gly465Glu | missense_variant | 1/1 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
LHON
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Leber optic atrophy Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1993 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Mitochondrial disease Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Nov 13, 2023 | The m.13730G>A (p.G465E) variant in MT-ND5 has been reported in one individual from one family to date (PMID: 8213825), in a male with Leber Hereditary Optic Neuropathy (LHON). The variant was present at 80% heteroplasmy in blood. The variant was presumed to have occurred de novo as it was absent in blood from his mother, maternal grandmother, and two maternal uncles (PMID: 8213825), however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.83, which predicts a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
Hmtvar
Pathogenic
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
DEOGEN2
Uncertain
D
LIST_S2
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A
PROVEAN
Pathogenic
D
Sift4G
Pathogenic
D
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at