rs767725140
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_138773.4(SLC25A46):c.598G>A(p.Gly200Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000061 in 1,572,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
SLC25A46
NM_138773.4 missense
NM_138773.4 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 5.71
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A46 | NM_138773.4 | c.598G>A | p.Gly200Arg | missense_variant | 6/8 | ENST00000355943.8 | |
SLC25A46 | NM_001303249.3 | c.598G>A | p.Gly200Arg | missense_variant | 6/8 | ||
SLC25A46 | NM_001303250.3 | c.325G>A | p.Gly109Arg | missense_variant | 6/8 | ||
SLC25A46 | NR_138151.2 | n.711G>A | non_coding_transcript_exon_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A46 | ENST00000355943.8 | c.598G>A | p.Gly200Arg | missense_variant | 6/8 | 1 | NM_138773.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000724 AC: 11AN: 151920Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000139 AC: 31AN: 223664Hom.: 0 AF XY: 0.000115 AC XY: 14AN XY: 121806
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GnomAD4 exome AF: 0.0000598 AC: 85AN: 1420830Hom.: 0 Cov.: 25 AF XY: 0.0000594 AC XY: 42AN XY: 706724
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GnomAD4 genome AF: 0.0000724 AC: 11AN: 151920Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6AN XY: 74196
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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 | Invitae | Jul 24, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 200 of the SLC25A46 protein (p.Gly200Arg). This variant is present in population databases (rs767725140, gnomAD 0.1%). 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: 567704). 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: "Tolerated"; 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;M;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;D;T;D
Sift4G
Benign
T;D;T;T
Polyphen
0.93
.;P;.;.
Vest4
MutPred
0.71
.;Loss of ubiquitination at K197 (P = 0.0367);Loss of ubiquitination at K197 (P = 0.0367);.;
MVP
MPC
0.18
ClinPred
T
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