rs121908532

chr7-96121733-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_014251.3(SLC25A13):c.1763G>A(p.Arg588Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R588L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SLC25A13 NM_014251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.69

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical; Name=6 (size 19) in uniprot entity S2513_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_014251.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 7-96121733-C-T is Pathogenic according to our data. Variant chr7-96121733-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6007.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}. Variant chr7-96121733-C-T is described in Lovd as [Pathogenic]. Variant chr7-96121733-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A13	NM_014251.3	c.1763G>A	p.Arg588Gln	missense_variant	17/18	ENST00000265631.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A13	ENST00000265631.10	c.1763G>A	p.Arg588Gln	missense_variant	17/18	1	NM_014251.3	A1
SLC25A13	ENST00000416240.6	c.1766G>A	p.Arg589Gln	missense_variant	17/18	1		P5
SLC25A13	ENST00000494085.1	n.266G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251172 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neonatal intrahepatic cholestasis due to citrin deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam

Jun 30, 2022

- -

Citrullinemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 01, 2021

- -

Citrin deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2023

ClinVar contains an entry for this variant (Variation ID: 6007). 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. This variant disrupts the p.Arg588 amino acid residue in SLC25A13. Other variant(s) that disrupt this residue have been observed in individuals with SLC25A13-related conditions (PMID: 27829683), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects SLC25A13 function (PMID: 18367750). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC25A13 protein function. This missense change has been observed in individual(s) with citrin deficiency (PMID: 18392553, 36599957). 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 (rs121908532, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 588 of the SLC25A13 protein (p.Arg588Gln). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2018

- -

Citrullinemia type II Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 27, 2008

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.87		Loss of methylation at R588 (P = 0.0142);.;
MVP		0.95
MPC		0.56
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.93
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -14

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908532; hg19: chr7-95751045; COSMIC: COSV55709470; COSMIC: COSV55709470;