rs756882441
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_001379210.1(SLC25A26):c.803_809del(p.Glu268AlafsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
SLC25A26
NM_001379210.1 frameshift
NM_001379210.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.06
Genes affected
SLC25A26 (HGNC:20661): (solute carrier family 25 member 26) This gene is a member of the mitochondrial carrier family which includes nuclear-encoded transporters localized on the inner mitochondrial membranes. Members of the family transport important small molecules across the mitochondrial inner membrane. This protein is involved in the transport of S-adenosylmethionine (SAM) into the mitochondria. Mutations in this gene are associated with combined oxidative phosphorylation deficiency 28. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.516 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A26 | NM_001379210.1 | c.803_809del | p.Glu268AlafsTer39 | frameshift_variant | 10/10 | ENST00000354883.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A26 | ENST00000354883.11 | c.803_809del | p.Glu268AlafsTer39 | frameshift_variant | 10/10 | 2 | NM_001379210.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251160Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135730
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GnomAD4 exome AF: 0.000133 AC: 195AN: 1461674Hom.: 0 AF XY: 0.000139 AC XY: 101AN XY: 727120
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74464
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 23, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change results in a frameshift in the SLC25A26 gene (p.Glu180Alafs*39). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the SLC25A26 protein and extend the protein by 31 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SLC25A26-related conditions. ClinVar contains an entry for this variant (Variation ID: 377066). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 | Aug 30, 2022 | The c.803_809delAAGTTGG (p.E268Afs*39) alteration, located in exon 11 (coding exon 10) of the SLC25A26 gene, consists of a deletion of 7 nucleotides from position 803 to 809, causing a translational frameshift with a predicted alternate stop codon after 39 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at