1-235806053-G-C
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4_StrongBS1_Supporting
The NM_000081.4(LYST):c.3083C>G(p.Ser1028Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00093 ( 0 hom. )
Consequence
LYST
NM_000081.4 missense
NM_000081.4 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: 0.750
Genes affected
LYST (HGNC:1968): (lysosomal trafficking regulator) This gene encodes a protein that regulates intracellular protein trafficking in endosomes, and may be involved in pigmentation. Mutations in this gene are associated with Chediak-Higashi syndrome, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants, though the full-length nature of some of these variants has not been determined. [provided by RefSeq, Apr 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LYST. . Trascript score misZ 4.0845 (greater than threshold 3.09). GenCC has associacion of gene with Chediak-Higashi syndrome, attenuated Chédiak-Higashi syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.022809416).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000493 (75/152240) while in subpopulation NFE AF= 0.00097 (66/68014). AF 95% confidence interval is 0.000782. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LYST | NM_000081.4 | c.3083C>G | p.Ser1028Cys | missense_variant | 6/53 | ENST00000389793.7 | NP_000072.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LYST | ENST00000389793.7 | c.3083C>G | p.Ser1028Cys | missense_variant | 6/53 | 5 | NM_000081.4 | ENSP00000374443.2 |
Frequencies
GnomAD3 genomes 0.000493 AC: 75AN: 152122Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000462 AC: 116AN: 251048Hom.: 0 AF XY: 0.000442 AC XY: 60AN XY: 135756
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GnomAD4 exome AF: 0.000930 AC: 1359AN: 1461582Hom.: 0 Cov.: 32 AF XY: 0.000916 AC XY: 666AN XY: 727118
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GnomAD4 genome 0.000493 AC: 75AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74426
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Chédiak-Higashi syndrome Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 25, 2022 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1028 of the LYST protein (p.Ser1028Cys). This variant is present in population databases (rs150636017, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 296408). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 | Fulgent Genetics, Fulgent Genetics | Apr 05, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 03, 2019 | - - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 17, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2023 | Reported in patients with juvenile idiopathic arthritis, however segregation and detailed clinical information was not provided (Meng et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33408077) - |
LYST-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 29, 2024 | The LYST c.3083C>G variant is predicted to result in the amino acid substitution p.Ser1028Cys. This variant was reported in an individual with juvenile idiopathic arthritis (Table S5, Meng et al 2021. PubMed ID: 33408077). This variant is reported in 0.088% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too frequent to be a primary cause of disease. 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 | Feb 28, 2022 | The c.3083C>G (p.S1028C) alteration is located in exon 6 (coding exon 4) of the LYST gene. This alteration results from a C to G substitution at nucleotide position 3083, causing the serine (S) at amino acid position 1028 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autoinflammatory syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
0.075
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at