7-96121733-C-T

Variant names:

• chr7-96121733-C-T
• rs121908532
• NM_014251.3:c.1763G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.69
• Publications: 9 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.30459 (below the threshold of 3.09). Trascript score misZ: 1.1434 (below the threshold of 3.09). GenCC associations: The gene is linked to citrin deficiency, neonatal intrahepatic cholestasis due to citrin deficiency, citrullinemia, type II, adult-onset, citrullinemia type II.
• 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 VariationId is 6007.

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.1763G>A	p.Arg588Gln	missense	Exon 17 of 18	NP_055066.1	Q9UJS0-1
	SLC25A13	NM_001160210.2		c.1766G>A	p.Arg589Gln	missense	Exon 17 of 18	NP_001153682.1	Q9UJS0-2
	SLC25A13	NR_027662.2		n.1789G>A		non_coding_transcript_exon	Exon 16 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A13	ENST00000265631.10	TSL:1 MANE Select	c.1763G>A	p.Arg588Gln	missense	Exon 17 of 18	ENSP00000265631.6	Q9UJS0-1
	SLC25A13	ENST00000416240.6	TSL:1	c.1766G>A	p.Arg589Gln	missense	Exon 17 of 18	ENSP00000400101.2	Q9UJS0-2
	SLC25A13	ENST00000856215.1		c.1883G>A	p.Arg628Gln	missense	Exon 18 of 19	ENSP00000526274.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251172 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000501 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Citrin deficiency (1)
1	-	-	Citrullinemia (1)
1	-	-	Citrullinemia type II (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neonatal intrahepatic cholestasis due to citrin deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	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
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

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