rs148409403
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS1_Supporting
The NM_000081.4(LYST):c.10235G>A(p.Arg3412His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000905 in 1,614,148 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3412C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000081.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LYST | NM_000081.4 | c.10235G>A | p.Arg3412His | missense_variant | 45/53 | ENST00000389793.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LYST | ENST00000389793.7 | c.10235G>A | p.Arg3412His | missense_variant | 45/53 | 5 | NM_000081.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000703 AC: 107AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000676 AC: 170AN: 251326Hom.: 0 AF XY: 0.000780 AC XY: 106AN XY: 135828
GnomAD4 exome AF: 0.000926 AC: 1353AN: 1461872Hom.: 2 Cov.: 32 AF XY: 0.000932 AC XY: 678AN XY: 727236
GnomAD4 genome ? AF: 0.000703 AC: 107AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48AN XY: 74448
ClinVar
Submissions by phenotype
Chédiak-Higashi syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3412 of the LYST protein (p.Arg3412His). This variant is present in population databases (rs148409403, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary immunodeficiency (PMID: 27872624). ClinVar contains an entry for this variant (Variation ID: 525155). 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) performed at Invitae indicates that this missense variant is expected to disrupt LYST protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
LYST-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 01, 2023 | The LYST c.10235G>A variant is predicted to result in the amino acid substitution p.Arg3412His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.20% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-235866186-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2020 | The c.10235G>A (p.R3412H) alteration is located in exon 45 (coding exon 43) of the LYST gene. This alteration results from a G to A substitution at nucleotide position 10235, causing the arginine (R) at amino acid position 3412 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the LYST c.10235G>A alteration was observed in 0.07% (194/282734) of total alleles studied, with a frequency of 0.2% (21/10364) in the Ashkenazi Jewish subpopulation. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.R3412H alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 12, 2017 | - - |
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 13, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at