7-96121695-C-T

Position:

chr7-96121695-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.1801G>A(p.Glu601Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,988 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).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SLC25A13
NM_014251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1O: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]

SLC25A13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a region_of_interest Carrier domain (size 291) 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, 0.98

PP5

Variant 7-96121695-C-T is Pathogenic according to our data. Variant chr7-96121695-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21512.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, not_provided=1, Likely_pathogenic=2}. Variant chr7-96121695-C-T is described in Lovd as [Pathogenic]. Variant chr7-96121695-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A13	NM_014251.3 link	c.1801G>A	p.Glu601Lys	missense_variant	17/18	ENST00000265631.10	NP_055066.1	Q9UJS0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC25A13	ENST00000265631.10 link	c.1801G>A	p.Glu601Lys	missense_variant	17/18	1	NM_014251.3	ENSP00000265631.6	Q9UJS0-1
SLC25A13	ENST00000416240.6 link	c.1804G>A	p.Glu602Lys	missense_variant	17/18	1		ENSP00000400101.2	Q9UJS0-2
SLC25A13	ENST00000494085.1 link	n.304G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Citrin deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 601 of the SLC25A13 protein (p.Glu601Lys). This variant is present in population databases (rs80338727, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of citrin deficiency (PMID: 11793471, 14680984, 20927635). ClinVar contains an entry for this variant (Variation ID: 21512). 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: 23053473). 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. -

Citrullinemia, type II, adult-onset

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 16, 2024

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 22, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 21, 2024

Variant summary: SLC25A13 c.1801G>A (p.Glu601Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251090 control chromosomes. c.1801G>A has been reported in the literature in the singly heterozygous or presumed compound heterozygous state in multiple individuals affected with Citrullinemia Type II (example, Kobayashi_2003, Chen_2013, Saheki_2002, Yamaguchi_2002, Fu_2011). These data indicate that the variant may be associated with disease. Functional analysis found that a yeast strain lacking the corresponding gene could not grow when this variant was introduced during complementation analysis, suggesting a lethal metabolic defect in this model system; protein levels were not impacted when strains were grown with adequate supplementation (example, Wongkittichote_2013). In patient cells presumed compound heterozygous with p.Leu85Pro protein levels were undetectable (example, Fu_2011) however the mechanism of protein loss/instability was not explored. The following publications have been ascertained in the context of this evaluation (PMID: 23901231, 20927635, 14680984, 12111366, 23053473, 11793471). ClinVar contains an entry for this variant (Variation ID: 21512). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

0.99

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.99

MutPred

0.87

Gain of MoRF binding (P = 0.0081);.;

MVP

0.98

MPC

0.35

ClinPred

1.0

GERP RS

4.9

Varity_R

0.93

gMVP

0.93

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