rs370070995
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting
The NM_000081.4(LYST):c.7258G>A(p.Gly2420Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000855 in 1,602,814 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 0.00025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000068 ( 0 hom. )
Consequence
LYST
NM_000081.4 missense
NM_000081.4 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 3.60
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 0 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=0.069398046).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00025 (38/152000) while in subpopulation AMR AF= 0.00157 (24/15260). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 23 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 | UniProt |
|---|---|---|---|---|---|---|---|
| LYST | NM_000081.4 | c.7258G>A | p.Gly2420Arg | missense_variant | 26/53 | ENST00000389793.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LYST | ENST00000389793.7 | c.7258G>A | p.Gly2420Arg | missense_variant | 26/53 | 5 | NM_000081.4 | P1 |
Frequencies
GnomAD3 genomes 0.000250 AC: 38AN: 152000Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000996 AC: 25AN: 250990Hom.: 0 AF XY: 0.0000811 AC XY: 11AN XY: 135654
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GnomAD4 exome AF: 0.0000682 AC: 99AN: 1450814Hom.: 0 Cov.: 28 AF XY: 0.0000651 AC XY: 47AN XY: 722484
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GnomAD4 genome 0.000250 AC: 38AN: 152000Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23AN XY: 74240
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Chédiak-Higashi syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2420 of the LYST protein (p.Gly2420Arg). This variant is present in population databases (rs370070995, 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: 525152). 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 not 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. - |
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
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of helix (P = 0.027);
MVP
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