NM_014252.4:c.95C>G

Variant names:

• chr13-40799096-C-G
• rs121908536
• NM_014252.4:c.95C>G
• SLC25A15 p.Thr32Arg

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_014252.4(SLC25A15):​c.95C>G​(p.Thr32Arg) 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. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001443691: "In vitro overexpression studies of this variant showed that it diminished but does not completely abolish SLC25A15 protein function (PMID:16940241). Additional studies using fibroblasts from patients carrying this variant in the homozygous state also showed a reduction in protein function (PMID:16940241)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T32I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A15 NM_014252.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.73
• Publications: 4 publications found

Genes affected

SLC25A15 (HGNC:10985): (solute carrier family 25 member 15) This gene is a member of the mitochondrial carrier family. The encoded protein transports ornithine across the inner mitochondrial membrane from the cytosol to the mitochondrial matrix. The protein is an essential component of the urea cycle, and functions in ammonium detoxification and biosynthesis of the amino acid arginine. Mutations in this gene result in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. There is a pseudogene of this locus on the Y chromosome.[provided by RefSeq, May 2009]

SUGT1P3 (HGNC:):

TPTE2P5 (HGNC:42356): (TPTE2 pseudogene 5)

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001443691: "In vitro overexpression studies of this variant showed that it diminished but does not completely abolish SLC25A15 protein function (PMID: 16940241). Additional studies using fibroblasts from patients carrying this variant in the homozygous state also showed a reduction in protein function (PMID: 16940241)."; SCV003442208: Experimental studies have shown that this missense change affects SLC25A15 function (PMID: 16940241).; SCV006072932: The most pronounced variant effect results in <10% of normal activity (e.g. Camacho_2006). PMID: 16940241
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_014252.4
• 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 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.10098 (below the threshold of 3.09). Trascript score misZ: 1.3225 (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine translocase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 13-40799096-C-G is Pathogenic according to our data. Variant chr13-40799096-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014252.4. 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
	SLC25A15	NM_014252.4	MANE Select	c.95C>G	p.Thr32Arg	missense	Exon 3 of 7	NP_055067.1	Q9Y619
	TPTE2P5	NR_038258.1		n.2251G>C		non_coding_transcript_exon	Exon 8 of 8
	TPTE2P5	NR_038259.1		n.2080G>C		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A15	ENST00000338625.9	TSL:1 MANE Select	c.95C>G	p.Thr32Arg	missense	Exon 3 of 7	ENSP00000342267.4	Q9Y619
	SLC25A15	ENST00000707033.1		c.95C>G	p.Thr32Arg	missense	Exon 3 of 7	ENSP00000516711.1	Q9Y619
	SLC25A15	ENST00000899653.1		c.95C>G	p.Thr32Arg	missense	Exon 3 of 7	ENSP00000569712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.94
gMVP		0.97
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: 1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121908536;

hg19: chr13-41373232;