rs80338722

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

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.91
Variant links:
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]

Genome browser will be placed here

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
SLC25A13NM_014251.3 linkuse as main transcriptc.1177+1G>A splice_donor_variant ENST00000265631.10 NP_055066.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC25A13ENST00000265631.10 linkuse as main transcriptc.1177+1G>A splice_donor_variant 1 NM_014251.3 ENSP00000265631 A1Q9UJS0-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152190
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00135
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251386
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000653
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000650
AC:
95
AN:
1461810
Hom.:
0
Cov.:
31
AF XY:
0.0000729
AC XY:
53
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00237
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152308
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00135
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000360
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

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 providedliterature onlyOMIMMay 01, 2001- -
Pathogenic, criteria provided, single submitterclinical testingGenesolutions, Medical Genetics Institutes, Ho Chi Minh City, VietnamJun 30, 2022- -
Citrullinemia type II Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2001- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017The 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 providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 13, 2024- -
Citrin deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024This 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 providedclinical testingNatera, Inc.Sep 16, 2020- -
SLC25A13-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 20, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
30
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
A;A;A
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DL_spliceai
1.0
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338722; hg19: chr7-95813588; API