rs113209379

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_000081.4(LYST):​c.8027G>T​(p.Ser2676Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,600,428 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000099 ( 1 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 0.571
Variant links:
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 Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.01042375).
BP6
Variant 1-235744103-C-A is Benign according to our data. Variant chr1-235744103-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435789.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000815 (124/152114) while in subpopulation AFR AF= 0.0028 (116/41492). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LYSTNM_000081.4 linkc.8027G>T p.Ser2676Ile missense_variant Exon 30 of 53 ENST00000389793.7 NP_000072.2 Q99698-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LYSTENST00000389793.7 linkc.8027G>T p.Ser2676Ile missense_variant Exon 30 of 53 5 NM_000081.4 ENSP00000374443.2 Q99698-1

Frequencies

GnomAD3 genomes
AF:
0.000796
AC:
121
AN:
151996
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00271
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000590
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000199
AC:
50
AN:
251134
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.00278
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000987
AC:
143
AN:
1448314
Hom.:
1
Cov.:
27
AF XY:
0.0000873
AC XY:
63
AN XY:
721412
show subpopulations
Gnomad4 AFR exome
AF:
0.00314
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.09e-7
Gnomad4 OTH exome
AF:
0.000517
GnomAD4 genome
AF:
0.000815
AC:
124
AN:
152114
Hom.:
0
Cov.:
32
AF XY:
0.000659
AC XY:
49
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.00280
Gnomad4 AMR
AF:
0.000524
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000573
Hom.:
0
Bravo
AF:
0.000990
ESP6500AA
AF:
0.00363
AC:
16
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000222
AC:
27

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 18, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BP4 -

Chédiak-Higashi syndrome Uncertain:1Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Mar 27, 2017
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

LYST-related disorder Benign:1
Nov 15, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

Autoinflammatory syndrome Benign:1
Sep 05, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
19
DANN
Benign
0.93
DEOGEN2
Benign
0.20
T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.41
T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.010
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.8
L
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.12
Sift
Benign
0.057
T
Sift4G
Benign
0.12
T
Polyphen
0.0
B
Vest4
0.25
MVP
0.57
ClinPred
0.031
T
GERP RS
2.8
Varity_R
0.091
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs113209379; hg19: chr1-235907403; COSMIC: COSV67714973; COSMIC: COSV67714973; API