rs201045270
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7
The NM_000081.4(LYST):c.8151T>C(p.Ile2717Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000879 in 1,387,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000081.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000720 AC: 18AN: 249838Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135408
GnomAD4 exome AF: 0.0000850 AC: 105AN: 1235010Hom.: 0 Cov.: 20 AF XY: 0.0000863 AC XY: 54AN XY: 625754
GnomAD4 genome AF: 0.000112 AC: 17AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74392
ClinVar
Submissions by phenotype
not specified Uncertain:2
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Variant summary: LYST c.8151T>C (p.Ile2717Ile) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 249838 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.8151T>C in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 211413). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Chédiak-Higashi syndrome Uncertain:1
This sequence change affects codon 2717 of the LYST mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LYST protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201045270, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 211413). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn genetic diseases Uncertain:1
Occurs in the last base pair of the exon Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
LYST-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). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at