rs541276426

chr7-96321955-A-Gchr7-96321955-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:12
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A13	NM_014251.3	c.2T>C	p.Met1?	start_lost	1/18	ENST00000265631.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A13	ENST00000265631.10	c.2T>C	p.Met1?	start_lost	1/18	1	NM_014251.3	A1
SLC25A13	ENST00000416240.6	c.2T>C	p.Met1?	start_lost	1/18	1		P5
SLC25A13	ENST00000472162.2	c.2T>C	p.Met1?	start_lost, NMD_transcript_variant	1/5	4

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152140 Hom.: 3 Cov.: 33

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.: 1 AF XY: 0.000743 AC XY: 56 AN XY: 75366

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.: 1 Cov.: 31 AF XY: 0.000219 AC XY: 150 AN XY: 685950

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: 88 AN: 152252 Hom.: 3 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74452

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.: 0

Bravo AF: 0.000540

ExAC AF: 0.000511 AC: 55

Asia WGS AF: 0.00289 AC: 10 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2018	- -
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	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:1 Uncertain: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 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 15, 2023

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 v2 database, including 1 homozygote. An additional 3 homozygotes are reported in gnomAD v3 database. Nevertheless, c.2T>C has been reported in the literature in compound heterozygous individuals affected with Citrullinemia Type II (e.g. Zhang_2012, Nguyen_2023). Experimental evidence evaluating an impact on protein function in yeast, demonstrated the variant affects function, however, does not allow convincing conclusions about the variant effect in human cells (Wongkittichote_2013). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=10) and as pathogenic (n=1). 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

Invitae

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

- -

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	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Benign	23
Dann	Benign	0.94
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.069
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	-0.066	T
MutationTaster	Benign	1.0	D;D;D
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	T
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

Other links and lift over

dbSNP: rs541276426; hg19: chr7-95951267;