rs141028076
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_014252.4(SLC25A15):āc.564C>Gā(p.Phe188Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,892 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 (ā ā ). Synonymous variant affecting the same amino acid position (i.e. F188F) has been classified as Likely benign.
Frequency
Consequence
NM_014252.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A15 | NM_014252.4 | c.564C>G | p.Phe188Leu | missense_variant | 5/7 | ENST00000338625.9 | |
TPTE2P5 | NR_038259.1 | n.452-6681G>C | intron_variant, non_coding_transcript_variant | ||||
TPTE2P5 | NR_038258.1 | n.623-6681G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A15 | ENST00000338625.9 | c.564C>G | p.Phe188Leu | missense_variant | 5/7 | 1 | NM_014252.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251488Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727248
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 16, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 188 of the SLC25A15 protein (p.Phe188Leu). This variant is present in population databases (rs141028076, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of SLC25A15-related conditions (PMID: 19242930, 29554876). ClinVar contains an entry for this variant (Variation ID: 38399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC25A15 protein function. Experimental studies have shown that this missense change affects SLC25A15 function (PMID: 25818551, 26589310). 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 p.Phe188 amino acid residue in SLC25A15. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10369256, 12807890, 23430880). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at