chr1-235805825-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4BS1_Supporting
The NM_000081.4(LYST):c.3311G>A(p.Arg1104Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000239 in 1,613,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 0 hom. )
Consequence
LYST
NM_000081.4 missense
NM_000081.4 missense
Scores
5
7
7
Clinical Significance
Conservation
PhyloP100: 5.99
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, LYST
BP4
Computational evidence support a benign effect (MetaRNN=0.40072596).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000252 (368/1461614) while in subpopulation NFE AF= 0.000317 (353/1111858). AF 95% confidence interval is 0.00029. There are 0 homozygotes in gnomad4_exome. There are 164 alleles in male gnomad4_exome 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 | UniProt |
---|---|---|---|---|---|---|---|
LYST | NM_000081.4 | c.3311G>A | p.Arg1104Gln | missense_variant | 6/53 | ENST00000389793.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LYST | ENST00000389793.7 | c.3311G>A | p.Arg1104Gln | missense_variant | 6/53 | 5 | NM_000081.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000119 AC: 18AN: 151884Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000191 AC: 48AN: 250862Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135580
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GnomAD4 exome AF: 0.000252 AC: 368AN: 1461614Hom.: 0 Cov.: 32 AF XY: 0.000226 AC XY: 164AN XY: 727106
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GnomAD4 genome AF: 0.000118 AC: 18AN: 152002Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74288
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
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 | Invitae | Sep 27, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1104 of the LYST protein (p.Arg1104Gln). This variant is present in population databases (rs148299757, gnomAD 0.04%). 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: 450396). 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 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 | Revvity Omics, Revvity | Nov 27, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2017 | The R1104Q variant in the LYST gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1104Q variant is observed in 35/66666 (0.05%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The R1104Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1104Q as a variant of uncertain significance. - |
Meniere disease Uncertain:1
Uncertain significance, no assertion criteria provided | research | Center for Computational Biology & Bioinformatics, University of California, San Diego | Jun 03, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
0.47
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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