rs80338724

chr7-96121997-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_014251.3(SLC25A13):c.1592G>A(p.Gly531Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G531G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC25A13 NM_014251.3 missense, splice_region
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a region_of_interest Carrier domain (size 291) in uniprot entity S2513_HUMAN there are 39 pathogenic changes around while only 2 benign (95%) in NM_014251.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-96121997-C-T is Pathogenic according to our data. Variant chr7-96121997-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-96121997-C-T is described in Lovd as [Pathogenic]. Variant chr7-96121997-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A13	NM_014251.3	c.1592G>A	p.Gly531Asp	missense_variant, splice_region_variant	16/18	ENST00000265631.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A13	ENST00000265631.10	c.1592G>A	p.Gly531Asp	missense_variant, splice_region_variant	16/18	1	NM_014251.3	A1
SLC25A13	ENST00000416240.6	c.1595G>A	p.Gly532Asp	missense_variant, splice_region_variant	16/18	1		P5
SLC25A13	ENST00000494085.1	n.2G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251420 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.00000547 AC: 8 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Citrin deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 531 of the SLC25A13 protein (p.Gly531Asp). ClinVar contains an entry for this variant (Variation ID: 21509). This missense change has been observed in individual(s) with clinical features of citrin deficiency (PMID: 23701493, 26858187). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs80338724, gnomAD 0.006%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects SLC25A13 function (PMID: 23053473). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. -

Citrullinemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 16, 2020

- -

Citrullinemia, type II, adult-onset Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 22, 2022

- -

Neonatal intrahepatic cholestasis due to citrin deficiency Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.98		Loss of catalytic residue at A530 (P = 0.1432);.;
MVP		0.98
MPC		0.63
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
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: rs80338724; hg19: chr7-95751309;