7-96234796-T-C

Variant names:

• chr7-96234796-T-C
• rs6957975
• NM_014251.3:c.328+6A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014251.3(SLC25A13):​c.328+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,608,688 control chromosomes in the GnomAD database, including 329,405 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34153 hom., cov: 31)
  • Exomes 𝑓: 0.63 (295252 hom.)
• Consequence: SLC25A13 NM_014251.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009214
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -0.323
• Publications: 19 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-96234796-T-C is Benign according to our data. Variant chr7-96234796-T-C is described in ClinVar as Benign. ClinVar VariationId is 260371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A13	NM_014251.3	c.328+6A>G		splice_region_variant, intron_variant	Intron 4 of 17	ENST00000265631.10	NP_055066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A13	ENST00000265631.10	c.328+6A>G		splice_region_variant, intron_variant	Intron 4 of 17	1	NM_014251.3	ENSP00000265631.6
SLC25A13	ENST00000416240.6	c.328+6A>G		splice_region_variant, intron_variant	Intron 4 of 17	1		ENSP00000400101.2
SLC25A13	ENST00000472162.2	n.213-25819A>G		intron_variant	Intron 3 of 4	4		ENSP00000473505.1

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101194 AN: 151708 Hom.: 34132 Cov.: 31

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.658

GnomAD2 exomes AF: 0.616 AC: 154731 AN: 251160 AF XY: 0.607

Gnomad AFR exome AF: 0.748

Gnomad AMR exome AF: 0.619

Gnomad ASJ exome AF: 0.742

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.645

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.633 AC: 922545 AN: 1456882 Hom.: 295252 Cov.: 30 AF XY: 0.628 AC XY: 455201 AN XY: 725054

African (AFR) AF: 0.750 AC: 25020 AN: 33354

American (AMR) AF: 0.628 AC: 28065 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 19404 AN: 26084

East Asian (EAS) AF: 0.463 AC: 18351 AN: 39618

South Asian (SAS) AF: 0.460 AC: 39602 AN: 86152

European-Finnish (FIN) AF: 0.640 AC: 34126 AN: 53300

Middle Eastern (MID) AF: 0.588 AC: 3385 AN: 5758

European-Non Finnish (NFE) AF: 0.647 AC: 716452 AN: 1107704

Other (OTH) AF: 0.633 AC: 38140 AN: 60216

GnomAD4 genome AF: 0.667 AC: 101251 AN: 151806 Hom.: 34153 Cov.: 31 AF XY: 0.662 AC XY: 49059 AN XY: 74146

African (AFR) AF: 0.750 AC: 31085 AN: 41458

American (AMR) AF: 0.650 AC: 9919 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 2611 AN: 3466

East Asian (EAS) AF: 0.450 AC: 2316 AN: 5142

South Asian (SAS) AF: 0.461 AC: 2205 AN: 4784

European-Finnish (FIN) AF: 0.661 AC: 6901 AN: 10444

Middle Eastern (MID) AF: 0.614 AC: 178 AN: 290

European-Non Finnish (NFE) AF: 0.646 AC: 43883 AN: 67938

Other (OTH) AF: 0.653 AC: 1373 AN: 2102

Alfa AF: 0.655 Hom.: 98671

Bravo AF: 0.675

Asia WGS AF: 0.468 AC: 1627 AN: 3478

EpiCase AF: 0.651

EpiControl AF: 0.653

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 74.812% in gnomAD_Exomes) based on the frequency threshold of 1.504% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. 3 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neonatal intrahepatic cholestasis due to citrin deficiency Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Citrullinemia Benign:1

Nov 18, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Citrullinemia type II Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Citrin deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Citrullinemia, type II, adult-onset Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Citrullinemia type I Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		-0.32
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs6957975; hg19: chr7-95864108; COSMIC: COSV55707981;