rs80338715

Variant names:

• chr7-96321942-C-T
• rs80338715
• NM_014251.3:c.15G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-96321942-C-T
• chr7-96321942-C-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_014251.3(SLC25A13):​c.15G>A​(p.Lys5Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000721 in 1,386,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: SLC25A13 NM_014251.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 1.08
• Publications: 3 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), PanelApp Australia
• neonatal intrahepatic cholestasis due to citrin deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet
• citrullinemia type II

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 7-96321942-C-T is Pathogenic according to our data. Variant chr7-96321942-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A13	NM_014251.3	MANE Select	c.15G>A	p.Lys5Lys	splice_region synonymous	Exon 1 of 18	NP_055066.1	Q9UJS0-1
	SLC25A13	NM_001160210.2		c.15G>A	p.Lys5Lys	splice_region synonymous	Exon 1 of 18	NP_001153682.1	Q9UJS0-2
	SLC25A13	NR_027662.2		n.157G>A		splice_region non_coding_transcript_exon	Exon 1 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A13	ENST00000265631.10	TSL:1 MANE Select	c.15G>A	p.Lys5Lys	splice_region synonymous	Exon 1 of 18	ENSP00000265631.6	Q9UJS0-1
	SLC25A13	ENST00000416240.6	TSL:1	c.15G>A	p.Lys5Lys	splice_region synonymous	Exon 1 of 18	ENSP00000400101.2	Q9UJS0-2
	SLC25A13	ENST00000856215.1		c.15G>A	p.Lys5Lys	splice_region synonymous	Exon 1 of 19	ENSP00000526274.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000721 AC: 10 AN: 1386672 Hom.: 0 Cov.: 31 AF XY: 0.00000584 AC XY: 4 AN XY: 684940

African (AFR) AF: 0.00 AC: 0 AN: 28800

American (AMR) AF: 0.00 AC: 0 AN: 35550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24480

East Asian (EAS) AF: 0.000266 AC: 9 AN: 33792

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077430

Other (OTH) AF: 0.00 AC: 0 AN: 57552

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Citrin deficiency (1)
1	-	-	Citrullinemia, type II, adult-onset (1)
-	-	-	Neonatal intrahepatic cholestasis due to citrin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.84
PhyloP100		1.1
PromoterAI		-0.79	Under-expression
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: 0

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

Other links and lift over

dbSNP: rs80338715; hg19: chr7-95951254;