7-96121733-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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

Scores

10
8
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 7.69
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 Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a repeat Solcar 3 (size 88) in uniprot entity S2513_HUMAN there are 19 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: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}. 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 rank MANE Protein UniProt
SLC25A13NM_014251.3 linkc.1763G>A p.Arg588Gln missense_variant Exon 17 of 18 ENST00000265631.10 NP_055066.1 Q9UJS0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC25A13ENST00000265631.10 linkc.1763G>A p.Arg588Gln missense_variant Exon 17 of 18 1 NM_014251.3 ENSP00000265631.6 Q9UJS0-1
SLC25A13ENST00000416240.6 linkc.1766G>A p.Arg589Gln missense_variant Exon 17 of 18 1 ENSP00000400101.2 Q9UJS0-2
SLC25A13ENST00000494085.1 linkn.266G>A non_coding_transcript_exon_variant Exon 1 of 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
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
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:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Neonatal intrahepatic cholestasis due to citrin deficiency Pathogenic:1
Jun 30, 2022
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Feb 19, 2018
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Citrullinemia Pathogenic:1
Apr 01, 2021
Natera, Inc.
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Citrullinemia type II Pathogenic:1
Mar 27, 2008
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Citrin deficiency Pathogenic:1
Apr 06, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). 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. ClinVar contains an entry for this variant (Variation ID: 6007). 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. Experimental studies have shown that this missense change affects SLC25A13 function (PMID: 18367750). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. 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. -

not provided Uncertain:1
Jul 26, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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;.
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

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

Other links and lift over

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