chr13-40799183-G-A
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_014252.4(SLC25A15):c.182G>A(p.Arg61His) variant causes a missense change. The variant allele was found at a frequency of 0.00425 in 1,614,208 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014252.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SLC25A15 | NM_014252.4 | c.182G>A | p.Arg61His | missense_variant | Exon 3 of 7 | ENST00000338625.9 | NP_055067.1 | |
TPTE2P5 | NR_038258.1 | n.2164C>T | non_coding_transcript_exon_variant | Exon 8 of 8 | ||||
TPTE2P5 | NR_038259.1 | n.1993C>T | non_coding_transcript_exon_variant | Exon 6 of 6 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00283 AC: 431AN: 152198Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00235 AC: 591AN: 251426Hom.: 0 AF XY: 0.00227 AC XY: 309AN XY: 135908
GnomAD4 exome AF: 0.00440 AC: 6426AN: 1461892Hom.: 14 Cov.: 35 AF XY: 0.00427 AC XY: 3108AN XY: 727248
GnomAD4 genome AF: 0.00283 AC: 431AN: 152316Hom.: 1 Cov.: 32 AF XY: 0.00246 AC XY: 183AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
BS1 -
The R61H variant in the SLC25A15 gene has been reported as a rare variant identified in 12 patients with multiple sclerosis, but was also observed in 10 healthy controls (Traboulsee et al., 2017). The R61H variant is observed in 577/126660 (0.45%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The R61H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R61H as a variant of uncertain significance. -
The SLC25A15 p.Arg61His variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs34615430), ClinVar (classified as a VUS by GeneDx, EGL Genetics and Illumina and as likely benign by Invitae for hyperornithinemia-hyperammonemia-homocitrullinemia syndrome) and LOVD 3.0 (reported as likely benign). The variant was identified in control databases in 663 of 282814 chromosomes at a frequency of 0.002344 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 582 of 129132 chromosomes (freq: 0.004507), Other in 18 of 7228 chromosomes (freq: 0.00249), African in 23 of 24958 chromosomes (freq: 0.000922), Latino in 30 of 35438 chromosomes (freq: 0.000847) and European (Finnish) in 10 of 25122 chromosomes (freq: 0.000398); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg61 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
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SLC25A15: BS2 -
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Uncertain:1Benign:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
SLC25A15-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Intellectual disability Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at