rs754427464
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_138773.4(SLC25A46):āc.410A>Gā(p.His137Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000585 in 1,588,988 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 32)
Exomes š: 0.000059 ( 1 hom. )
Consequence
SLC25A46
NM_138773.4 missense
NM_138773.4 missense
Scores
5
12
2
Clinical Significance
Conservation
PhyloP100: 8.43
Genes affected
SLC25A46 (HGNC:25198): (solute carrier family 25 member 46) This gene encodes a mitochondrial solute carrier protein family member. It functions in promoting mitochondrial fission, and prevents the formation of hyperfilamentous mitochondria. Mutation of this gene results in neuropathy and optic atrophy. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.814
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC25A46 | NM_138773.4 | c.410A>G | p.His137Arg | missense_variant | 4/8 | ENST00000355943.8 | NP_620128.1 | |
SLC25A46 | NM_001303249.3 | c.410A>G | p.His137Arg | missense_variant | 4/8 | NP_001290178.1 | ||
SLC25A46 | NM_001303250.3 | c.137A>G | p.His46Arg | missense_variant | 4/8 | NP_001290179.1 | ||
SLC25A46 | NR_138151.2 | n.523A>G | non_coding_transcript_exon_variant | 4/9 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000577 AC: 13AN: 225452Hom.: 0 AF XY: 0.0000816 AC XY: 10AN XY: 122620
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GnomAD4 exome AF: 0.0000592 AC: 85AN: 1436790Hom.: 1 Cov.: 28 AF XY: 0.0000671 AC XY: 48AN XY: 714820
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuropathy, hereditary motor and sensory, type 6B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 19, 2022 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 137 of the SLC25A46 protein (p.His137Arg). This variant is present in population databases (rs754427464, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SLC25A46-related conditions. ClinVar contains an entry for this variant (Variation ID: 570160). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2020 | The p.H137R variant (also known as c.410A>G), located in coding exon 4 of the SLC25A46 gene, results from an A to G substitution at nucleotide position 410. The histidine at codon 137 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a compound heterozygous state with a different SLC25A46 alteration in an individual presenting with Parkinson's disease and optic atrophy (Bitetto G et al. Parkinsonism Relat Disord, 2020 05;74:1-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.0514);Gain of solvent accessibility (P = 0.0514);
MVP
MPC
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