rs202247807
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_014252.4(SLC25A15):c.823C>T(p.Arg275Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,611,904 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
SLC25A15
NM_014252.4 stop_gained
NM_014252.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.84
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-40809584-C-T is Pathogenic according to our data. Variant chr13-40809584-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A15 | NM_014252.4 | c.823C>T | p.Arg275Ter | stop_gained | 7/7 | ENST00000338625.9 | |
TPTE2P5 | NR_038259.1 | n.452-8860G>A | intron_variant, non_coding_transcript_variant | ||||
TPTE2P5 | NR_038258.1 | n.623-8860G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A15 | ENST00000338625.9 | c.823C>T | p.Arg275Ter | stop_gained | 7/7 | 1 | NM_014252.4 | P1 | |
SLC25A15 | ENST00000707033.1 | c.823C>T | p.Arg275Ter | stop_gained | 7/7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251146Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135722
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GnomAD4 exome AF: 0.00000548 AC: 8AN: 1459806Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726226
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GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74280
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 29, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change creates a premature translational stop signal (p.Arg275*) in the SLC25A15 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the SLC25A15 protein. This variant is present in population databases (rs202247807, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (PMID: 16376511, 23430880). ClinVar contains an entry for this variant (Variation ID: 38403). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the C-terminus of the SLC25A15 protein. Other variant(s) that disrupt this region (p.Glu288Glyfs*3) have been observed in individuals with SLC25A15-related conditions (PMID: 11552031, 12807890). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 13, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at