NM_014251.3:c.674C>G

Variant names:

• chr7-96191189-G-C
• rs80338719
• NM_014251.3:c.674C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_014251.3(SLC25A13):​c.674C>G​(p.Ser225Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S225L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A13 NM_014251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 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: Uncertain_significance. The variant received 4 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, 0.788

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A13	NM_014251.3	MANE Select	c.674C>G	p.Ser225Trp	missense	Exon 7 of 18	NP_055066.1
	SLC25A13	NM_001160210.2		c.674C>G	p.Ser225Trp	missense	Exon 7 of 18	NP_001153682.1
	SLC25A13	NR_027662.2		n.700C>G		non_coding_transcript_exon	Exon 6 of 17

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A13	ENST00000265631.10	TSL:1 MANE Select	c.674C>G	p.Ser225Trp	missense	Exon 7 of 18	ENSP00000265631.6
	SLC25A13	ENST00000416240.6	TSL:1	c.674C>G	p.Ser225Trp	missense	Exon 7 of 18	ENSP00000400101.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.51		Gain of MoRF binding (P = 0.1191)
MVP		0.97
MPC		0.63
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.81
gMVP		0.77
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs80338719; hg19: chr7-95820501;