rs113209379

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP2BP4_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

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]

LYST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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=0.01042375).

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: {Likely_benign=3, Uncertain_significance=3}.

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/exons	MANE	UniProt
LYST	NM_000081.4 linkuse as main transcript	c.8027G>T	p.Ser2676Ile	missense_variant	30/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7 linkuse as main transcript	c.8027G>T	p.Ser2676Ile	missense_variant	30/53	5	NM_000081.4	P1	Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.000796

AC:

121

AN:

151996

Hom.:

Cov.:

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:

AN:

251134

Hom.:

AF XY:

0.000147

AC XY:

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.:

Cov.:

AF XY:

0.0000873

AC XY:

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.:

Cov.:

AF XY:

0.000659

AC XY:

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.:

Bravo

AF:

0.000990

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

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

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2022	BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Chédiak-Higashi syndrome

Uncertain:1Benign:1

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 27, 2017

- -

LYST-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Benign

0.93

DEOGEN2

Benign

0.20

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.41

M_CAP

Benign

0.037

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.97

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.0

REVEL

Benign

0.12

Sift

Benign

0.057

Sift4G

Benign

0.12

Polyphen

0.0

Vest4

0.25

MVP

0.57

ClinPred

0.031

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over