7-96189371-TCATA-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting

The NM_014251.3(SLC25A13):c.852_855delTATG(p.Met285ProfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,614,136 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

SLC25A13
NM_014251.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 9.25

Publications

41 publications found

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 Gene-Disease associations (from GenCC):

citrin deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
citrullinemia, type II, adult-onset
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
citrullinemia type II
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
neonatal intrahepatic cholestasis due to citrin deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC25A13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-96189371-TCATA-T is Pathogenic according to our data. Variant chr7-96189371-TCATA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 225472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A13	NM_014251.3 link	c.852_855delTATG	p.Met285ProfsTer2	frameshift_variant	Exon 9 of 18	ENST00000265631.10	NP_055066.1	Q9UJS0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC25A13	ENST00000265631.10 link	c.852_855delTATG	p.Met285ProfsTer2	frameshift_variant	Exon 9 of 18	1	NM_014251.3	ENSP00000265631.6	Q9UJS0-1
SLC25A13	ENST00000416240.6 link	c.852_855delTATG	p.Met285ProfsTer2	frameshift_variant	Exon 9 of 18	1		ENSP00000400101.2	Q9UJS0-2
SLC25A13	ENST00000484495.5 link	n.5_8delTATG		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00539

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

GnomAD2 exomes

AF:

0.000334

AC:

AN:

251422

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

155

AN:

1461832

Hom.:

AF XY:

0.0000880

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00378

AC:

150

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111970

Other (OTH)

AF:

0.0000828

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000197

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41582

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00540

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000126

Hom.:

Bravo

AF:

0.000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neonatal intrahepatic cholestasis due to citrin deficiency

Pathogenic:5

Jun 30, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

Mar 05, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.033%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000225472 /PMID: 10369257). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

PVS1+PM3_VS+PP1_M+PP4 -

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Citrullinemia type II

Pathogenic:4

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC25A13 c.852_855delTATG (p.Met285ProfsTer2) variant, also referred to in the literature as c.851_854del and c.851del4, is a frameshift variant that leads to premature truncation of the protein, and is one of the most common pathogenic variants in Japanese persons with citrin deficiency. Across a selection of available literature, the p.Met285ProfsTer2 variant has been identified in a homozygous state in 30 patients, in a compound heterozygous state in 27 patients, and in a heterozygous state in two patients in whom a second variant was not identified (Kobayashi et al. 1999; Ohura et al. 2001; Tamamori et al. 2002; Song et al. 2011). The p.Met285ProfsTer2 variant was absent from 127 controls and is reported at a frequency of 0.01515 in the Kinh in Ho Chi Minh City, Vietnam population of the 1000 Genomes Project. Based on the collective evidence and the potential impact of frameshift variants, the p.Met285ProfsTer2 variant is classified as pathogenic for citrin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

May 09, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC25A13 c.852_855delTATG (p.Met285ProfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00033 in 251422 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC25A13 causing Citrullinemia Type II (0.00033 vs 0.0011), allowing no conclusion about variant significance. c.852_855delTATG has been widely reported in the literature in multiple individuals affected with Citrullinemia Type II (example, Zong Song_2011). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:3

Jul 13, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 29, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 25, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26852511, 27779681, 23022256, 19470249, 17880783, 10369257, 27405544, 12512993, 27347070, 27577219, 29659898, 26858187, 29152073, 29651749, 30591617, 29961769, 16059747, 31620407, 31607264, 29625052, 31845334, 26689913, 33817322, 34426522, 33627582, 31589614, 32289814, 33763395, 33176737, 28981931, 33497767, 33611823) -

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

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1+PM3_VeryStrong -

Apr 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Citrullinemia, type II, adult-onset

Pathogenic:1Other:1

Mar 30, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Citrin deficiency

Pathogenic:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Met285Profs*2) in the SLC25A13 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A13 are known to be pathogenic (PMID: 10369257, 14680984, 27405544). This variant is present in population databases (rs569808959, gnomAD 0.5%). This premature translational stop signal has been observed in individual(s) with citrin deficiency (PMID: 10369257, 12512993, 23022256, 23067347, 26852511, 27347070, 27405544, 27577219, 27578510). It has also been observed to segregate with disease in related individuals. This variant is also known as c.851del4. ClinVar contains an entry for this variant (Variation ID: 225472). For these reasons, this variant has been classified as Pathogenic. -

CITRIN DEFICIENCY, NEONATAL ONSET

Pathogenic:1

Nov 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Late-onset citrullinemia

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

SLC25A13-related disorder

Pathogenic:1

Dec 11, 2022

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC25A13 c.852_855delTATG variant is predicted to result in a frameshift and premature protein termination (p.Met285Profs*2). This variant is commonly reported to be causative for citrin deficiency in Asian populations (e.g., Kobayashi et al. 1999. PubMed ID: 10369257, reported as 851del4; Lin et al. 2016. PubMed ID: 27405544, reported as c.851_854del4). Many other predicted loss-of-function variants in SLC25A13 have been reported in association with citrullinemia type 2 and/or neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) (ClinVar database; Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). We classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over