rs104894429
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014252.4(SLC25A15):c.535C>T(p.Arg179Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,104 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_014252.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC25A15 | NM_014252.4 | c.535C>T | p.Arg179Ter | stop_gained | 5/7 | ENST00000338625.9 | NP_055067.1 | |
TPTE2P5 | NR_038259.1 | n.452-6652G>A | intron_variant, non_coding_transcript_variant | |||||
TPTE2P5 | NR_038258.1 | n.623-6652G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC25A15 | ENST00000338625.9 | c.535C>T | p.Arg179Ter | stop_gained | 5/7 | 1 | NM_014252.4 | ENSP00000342267 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251486Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135918
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727228
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74448
ClinVar
Submissions by phenotype
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Pathogenic:4Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change creates a premature translational stop signal (p.Arg179*) in the SLC25A15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A15 are known to be pathogenic (PMID: 11552031, 19242930). This variant is present in population databases (rs104894429, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (PMID: 10805333, 11355015, 12807890, 19242930, 24473688). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5994). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
SLC25A15-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 13, 2022 | The SLC25A15 c.535C>T variant is predicted to result in premature protein termination (p.Arg179*). This variant has been reported in individuals with hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome (Tsujino et al. 2000. PubMed ID: 10805333; Miyamoto et al. 2001. PubMed ID: 11355015). Functional studies have shown that this variant results in a truncated protein when exogenously expressed and that this protein is biochemically non-functional (Fiermonte et al. 2003. PubMed ID: 12807890). This variant is reported in 0.065% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-41381512-C-T). Nonsense variants in SLC25A15 are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/5994). Given all the evidence, we interpret c.535C>T (p.Arg179*) as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at