rs80338722
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The ENST00000265631.10(SLC25A13):c.1177+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000065 ( 0 hom. )
Consequence
SLC25A13
ENST00000265631.10 splice_donor
ENST00000265631.10 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.91
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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07790927 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 47, new splice context is: aagGTttgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-96184276-C-T is Pathogenic according to our data. Variant chr7-96184276-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-96184276-C-T is described in Lovd as [Pathogenic]. Variant chr7-96184276-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC25A13 | NM_014251.3 | c.1177+1G>A | splice_donor_variant | ENST00000265631.10 | NP_055066.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC25A13 | ENST00000265631.10 | c.1177+1G>A | splice_donor_variant | 1 | NM_014251.3 | ENSP00000265631 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152190Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251386Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135864
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GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461810Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53AN XY: 727204
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74480
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neonatal intrahepatic cholestasis due to citrin deficiency Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam | Jun 30, 2022 | - - |
Citrullinemia type II Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The SLC25A13 c.1177+1G>A variant, which occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product, is a common pathogenic variant in Japanese individuals with citrin deficiency (Kobayashi et al. 2005). Across a selection of available literature, the c.1177+1G>A variant has been identified in a homozygous state in 11 patients and in a compound heterozygous state in at least three patients (Kobayashi et al. 1999; Ohura et al. 2001; Tamamori et al. 2002; Liu et al. 2014). The c.1177+1G>A variant was absent from 234 controls and is reported at a frequency of 0.01923 in the Japanese in Tokyo, Japan population of the 1000 Genomes Project. Based on the evidence from the literature and the potential impact of splice donor variants, the c.1177+1G>A variant is classified as pathogenic for citrin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
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 | Feb 13, 2024 | - - |
Citrin deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This sequence change affects a donor splice site in intron 11 of the SLC25A13 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs80338722, gnomAD 0.07%). Disruption of this splice site has been observed in individuals with citrin deficiency (PMID: 10369257, 12424587, 12512993, 22710133, 23430852). This variant is also known as IVS11+1G>A. ClinVar contains an entry for this variant (Variation ID: 6002). Studies have shown that disruption of this splice site results in skipping of exon 11, but is expected to preserve the integrity of the reading-frame (PMID: 22710133). For these reasons, this variant has been classified as Pathogenic. - |
Late-onset citrullinemia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
SLC25A13-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 20, 2024 | The SLC25A13 c.1177+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, which is also described as IVS11+1G>A in the literature, has been reported in the homozygous or compound heterozygous state with a second causative SLC25A13 variant in multiple patients with citrin deficiency (e.g., Kobayashi et al. 1999. PubMed ID: 10369257, also referred to as Mutation II; Hayasaka et al. 2012. PubMed ID: 23430852; Lin et al. 2012. PubMed ID: 22710133; Togawa et al. 2016. PubMed ID: 26858187; Lin et al. 2020. PubMed ID: 31845334). RNA studies have shown that the c.1177+1G>A variant results in skipping of SLC25A13 exon 11 (Kobayashi et al. 1999. PubMed ID: 10369257; Lin et al. 2012. PubMed ID: 22710133). Many splicing and loss-of-function variants have been reported to be causative for SLC25A13-related disorders (e.g., Lin et al. 2016. PubMed ID: 27405544). In summary, we interpret this variant as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at