rs80338725
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_014251.3(SLC25A13):c.1660_1661insGAGATTACAGGTGGCTGCCCGGG(p.Ala554GlyfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SLC25A13
NM_014251.3 frameshift
NM_014251.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
SLC25A13 (HGNC:10983): (solute carrier family 25 member 13) This gene is a member of the mitochondrial carrier family. The encoded protein contains four EF-hand Ca(2+) binding motifs in the N-terminal domain, and localizes to mitochondria. The protein catalyzes the exchange of aspartate for glutamate and a proton across the inner mitochondrial membrane, and is stimulated by calcium on the external side of the inner mitochondrial membrane. Mutations in this gene result in citrullinemia, type II. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 7-96121928-G-GCCCGGGCAGCCACCTGTAATCTC is Pathogenic according to our data. Variant chr7-96121928-G-GCCCGGGCAGCCACCTGTAATCTC is described in ClinVar as [Pathogenic]. Clinvar id is 6003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC25A13 | NM_014251.3 | c.1660_1661insGAGATTACAGGTGGCTGCCCGGG | p.Ala554GlyfsTer17 | frameshift_variant | 16/18 | ENST00000265631.10 | NP_055066.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC25A13 | ENST00000265631.10 | c.1660_1661insGAGATTACAGGTGGCTGCCCGGG | p.Ala554GlyfsTer17 | frameshift_variant | 16/18 | 1 | NM_014251.3 | ENSP00000265631 | A1 | |
SLC25A13 | ENST00000416240.6 | c.1663_1664insGAGATTACAGGTGGCTGCCCGGG | p.Ala555GlyfsTer17 | frameshift_variant | 16/18 | 1 | ENSP00000400101 | P5 | ||
SLC25A13 | ENST00000494085.1 | n.70_71insGAGATTACAGGTGGCTGCCCGGG | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251412Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135876
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727246
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74434
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neonatal intrahepatic cholestasis due to citrin deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam | Jun 30, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital | - | PVS1+PM3_VS+PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 11, 2022 | PM2, PM3_strong, PVS1 - |
Citrullinemia type II Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2023 | Variant summary: SLC25A13 c.1638_1660dup23 (p.Ala554GlyfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.1799dup [p.Tyr600Ter], c.1813C>T [p.Arg605Ter]). The variant allele was found at a frequency of 8.8e-05 in 251412 control chromosomes (gnomAD), predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SLC25A13 causing Citrullinemia Type II (8.8e-05 vs 0.0012), allowing no conclusion about variant significance. c.1638_1660dup23 has been reported in the literature as a biallelic genotype in multiple individuals affected with Citrullinemia (e.g. Song_2011, Wang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Citrullinemia, type II, adult-onset Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Citrin deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Ala554Glyfs*17) in the SLC25A13 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A13 are known to be pathogenic (PMID: 10369257, 14680984, 27405544). This variant is present in population databases (rs80338725, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with SLC25A13-related conditions (PMID: 27405544). ClinVar contains an entry for this variant (Variation ID: 6003). For these reasons, this variant has been classified as Pathogenic. - |
SLC25A13-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 22, 2024 | The SLC25A13 c.1638_1660dup23 variant is predicted to result in a frameshift and premature protein termination (p.Ala554Glyfs*17). This variant has been reported in numerous pediatric patients with intrahepatic cholestasis with citrin deficiency (Lin WX et al 2016. PubMed ID: 27405544; Nguyen MT et al 2023. PubMed ID: 36599957; Wang NL et al 2019. PubMed ID: 31450232; Song YZ et al 2011. PubMed ID: 21424115) and patients with adult-onset type II citrullinemia (Kobayashi K et al 1999. PubMed ID: 10369257). This variant is almost always reported in a compound heterozygous state with another variant within SLC25A13 (Lin WX et al 2016. PubMed ID: 27405544; Song YZ et al 2011. PubMed ID: 21424115; Wang NL et al 2019. PubMed ID: 31450232), and has been reported in 4 homozygotes as well (Wang NL et al 2019. PubMed ID: 31450232). This variant is reported in 0.12% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in SLC25A13 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at