22-19176228-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_005984.5(SLC25A1):c.838G>A(p.Val280Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SLC25A1
NM_005984.5 missense
NM_005984.5 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: -0.0580
Genes affected
SLC25A1 (HGNC:10979): (solute carrier family 25 member 1) This gene encodes a member of the mitochondrial carrier subfamily of solute carrier proteins. Members of this family include nuclear-encoded transporters that translocate small metabolites across the mitochondrial membrane. This protein regulates the movement of citrate across the inner membranes of the mitochondria. Mutations in this gene have been associated with combined D-2- and L-2-hydroxyglutaric aciduria. Pseudogenes of this gene have been identified on chromosomes 7, 11, 16, and 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005984.5
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.11145216).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A1 | NM_005984.5 | c.838G>A | p.Val280Ile | missense_variant | 9/9 | ENST00000215882.10 | |
SLC25A1 | NM_001256534.2 | c.859G>A | p.Val287Ile | missense_variant | 8/8 | ||
SLC25A1 | NM_001287387.2 | c.529G>A | p.Val177Ile | missense_variant | 9/9 | ||
SLC25A1 | NR_046298.3 | n.762G>A | non_coding_transcript_exon_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A1 | ENST00000215882.10 | c.838G>A | p.Val280Ile | missense_variant | 9/9 | 1 | NM_005984.5 | P1 | |
SLC25A1 | ENST00000451283.5 | c.529G>A | p.Val177Ile | missense_variant | 9/9 | 2 | |||
SLC25A1 | ENST00000470922.5 | n.980G>A | non_coding_transcript_exon_variant | 8/8 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250638Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135606
GnomAD3 exomes
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250638
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135606
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2AN: 1460678Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726676
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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2
AN:
1460678
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Cov.:
33
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0
AN XY:
726676
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Alfa
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EpiControl
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 23, 2021 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SLC25A1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 280 of the SLC25A1 protein (p.Val280Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Loss of methylation at R282 (P = 0.1412);.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at