rs541276426

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_014251.3(SLC25A13):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,541,380 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00058 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

SLC25A13
NM_014251.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:15

Conservation

PhyloP100: 2.23

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]

SLC25A13 links:

SLC25A13 (HGNC:):

SLC25A13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Start lost variant, no new inframe start found.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A13	NM_014251.3 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/18	ENST00000265631.10	NP_055066.1	Q9UJS0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC25A13	ENST00000265631.10 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/18	1	NM_014251.3	ENSP00000265631.6	Q9UJS0-1
SLC25A13	ENST00000416240.6 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/18	1		ENSP00000400101.2	Q9UJS0-2
SLC25A13	ENST00000472162.2 linkuse as main transcript	n.2T>C		non_coding_transcript_exon_variant	1/5	4		ENSP00000473505.1	R4GN64

Frequencies

GnomAD3 genomes

AF:

0.000592

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0166

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000839

AC:

115

AN:

137038

Hom.:

AF XY:

0.000743

AC XY:

AN XY:

75366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000416

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0117

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000565

Gnomad OTH exome

AF:

0.000261

GnomAD4 exome

AF:

0.000199

AC:

277

AN:

1389128

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

150

AN XY:

685950

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000279

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00714

Gnomad4 SAS exome

AF:

0.0000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.000347

GnomAD4 genome

AF:

0.000578

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0163

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000856

Hom.:

Bravo

AF:

0.000540

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3472

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2018	The c.2 T>C variant and a missense variant were identified in both an infant with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the infants unaffected father; the mother was heterozygous for c.2 T>C (Zeng et al. 2014). Found in other patients with NICCD in whom a second SLC25A13 variant was not identified (Treepongkaruna et al. 2012). Functional studies in yeast found c.2 T>C expresses a truncated protein which was not functional; however, no studies have evaluated the effect of this variant in human cells (Wongkittichote et al. 2013). The c.2 T>C variant was found to have a carrier frequency of 1/18 in a Thai population ( Wongkittichote et al. 2013). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 28, 2021	- -

Neonatal intrahepatic cholestasis due to citrin deficiency

Pathogenic:1Uncertain:1

Pathogenic, flagged submission	clinical testing	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	Jun 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neonatal-onset citrullinemia type II (MIM# 605814) and adult-onset citrullinemia type II (MIM#603471). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (84 heterozygotes, 3 homozygotes). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as VUS in ClinVar. It has also been reported multiple times as homozygous or compound heterozygous in individuals with neonatal intrahepatic cholestasis caused by citrin deficiency (PMID: 23022256, 23067347, 25216257, 27405544, 30887117, 34704407). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in yeast found this variant expresses a truncated protein which was not functional (PMID: 23053473). (SP) 0710 - Another start loss variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change c.2T>A has been reported as VUS in ClinVar. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Neonatal intrahepatic cholestasis due to citrin deficiency;CN295299:Citrullinemia, type II, adult-onset

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1_Supporting+PM3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 12, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 09, 2024

Variant summary: SLC25A13 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame methionine is present at codon 34. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 137038 control chromosomes, predominantly at a frequency of 0.012 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.39 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC25A13 causing Citrullinemia Type II phenotype (0.0035). c.2T>C has been reported in the literature in multiple individuals affected with Citrullinemia Type II (e.g. Zhang_2012, Chen_2022, Nguyen_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect in human cells (Wongkittichote_2013). The following publications have been ascertained in the context of this evaluation (PMID: 25216257, 27405544, 31180159, 34800434, 36599957, 23067347, 23053473, 23022256, 35798653). ClinVar contains an entry for this variant (Variation ID: 193371). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Citrullinemia type II

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Citrin deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change affects the initiator methionine of the SLC25A13 mRNA. The next in-frame methionine is located at codon 34. This variant is present in population databases (rs541276426, gnomAD 1.2%), including at least one homozygous and/or hemizygous individual. Disruption of the initiator codon has been observed in individual(s) with citrin deficiency (PMID: 25216257, 27405544). ClinVar contains an entry for this variant (Variation ID: 193371). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects SLC25A13 function (PMID: 23053473). 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. -

Citrullinemia, type II, adult-onset

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 26, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Late-onset citrullinemia

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

SLC25A13-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2024

The SLC25A13 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in patients with citrin deficiency (Zeng et al. 2014. PubMed ID: 25216257; Lin et al. 2016. PubMed ID: 27405544). Additionally, this variant was reported in a patient with neonatal intrahepatic cholestasis but was also observed in unaffected controls (Treepongkaruna et al. 2012. PubMed ID: 23067347). Functional studies in a yeast model system suggest that the c.2T>C variant produces a non-functional truncated protein product designated p.Met1_Phe34del (Wongkittichote et al. 2013. PubMed ID: 23053473). However, the c.2T>C variant has not been evaluated in human cells. Of note, this variant has been observed with an allele frequency up to ~1.2%, including one homozygote, in a large database of individuals with unknown phenotype. Although we suspect this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Citrullinemia type I

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

0.069

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

-0.066

PROVEAN

Benign

0.57

N;N

REVEL

Uncertain

0.54

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.46

P;.

Vest4

0.88

MutPred

0.56

Gain of glycosylation at M1 (P = 0.0152);Gain of glycosylation at M1 (P = 0.0152);

MVP

0.93

ClinPred

0.27

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over