chr14-36684771-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_030631.4(SLC25A21):c.758C>T(p.Thr253Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000028 in 1,609,066 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
SLC25A21
NM_030631.4 missense
NM_030631.4 missense
Scores
9
6
3
Clinical Significance
Conservation
PhyloP100: 6.11
Genes affected
SLC25A21 (HGNC:14411): (solute carrier family 25 member 21) SLC25A21 is a homolog of the S. cerevisiae ODC proteins, mitochondrial carriers that transport C5-C7 oxodicarboxylates across inner mitochondrial membranes. One of the species transported by ODC is 2-oxoadipate, a common intermediate in the catabolism of lysine, tryptophan, and hydroxylysine in mammals. Within mitochondria, 2-oxoadipate is converted into acetyl-CoA.[supplied by OMIM, Apr 2004]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.849
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A21 | NM_030631.4 | c.758C>T | p.Thr253Ile | missense_variant | 8/10 | ENST00000331299.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A21 | ENST00000331299.6 | c.758C>T | p.Thr253Ile | missense_variant | 8/10 | 1 | NM_030631.4 | P4 | |
SLC25A21 | ENST00000555449.5 | c.758C>T | p.Thr253Ile | missense_variant | 8/11 | 2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000122 AC: 3AN: 246870Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133336
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GnomAD4 exome AF: 0.0000302 AC: 44AN: 1456954Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 724596
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
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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 | Aug 10, 2022 | 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals affected with SLC25A21-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 253 of the SLC25A21 protein (p.Thr253Ile). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
M;M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.98
.;D
Vest4
MutPred
Loss of phosphorylation at T249 (P = 0.1023);Loss of phosphorylation at T249 (P = 0.1023);
MVP
MPC
0.57
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -27
Find out detailed SpliceAI scores and Pangolin per-transcript scores at