NM_000081.4:c.5945C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000081.4(LYST):c.5945C>T(p.Thr1982Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00949 in 1,610,604 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 76 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.56

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

Chediak-Higashi syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
attenuated Chédiak-Higashi syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LYST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058999956).

BP6

Variant 1-235766255-G-A is Benign according to our data. Variant chr1-235766255-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00641 (975/152176) while in subpopulation NFE AF = 0.0113 (765/67980). AF 95% confidence interval is 0.0106. There are 7 homozygotes in GnomAd4. There are 408 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4 link	c.5945C>T	p.Thr1982Ile	missense_variant	Exon 21 of 53	ENST00000389793.7	NP_000072.2	Q99698-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7 link	c.5945C>T	p.Thr1982Ile	missense_variant	Exon 21 of 53	5	NM_000081.4	ENSP00000374443.2		Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.00641

AC:

975

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.00293

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00597

AC:

1480

AN:

247718

AF XY:

0.00591

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00270

Gnomad ASJ exome

AF:

0.00192

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00292

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00615

GnomAD4 exome

AF:

0.00981

AC:

14303

AN:

1458428

Hom.:

Cov.:

AF XY:

0.00955

AC XY:

6930

AN XY:

725596

show subpopulations

African (AFR)

AF:

0.00150

AC:

AN:

33238

American (AMR)

AF:

0.00310

AC:

137

AN:

44226

Ashkenazi Jewish (ASJ)

AF:

0.00219

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.000665

AC:

AN:

85670

European-Finnish (FIN)

AF:

0.00354

AC:

189

AN:

53330

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0119

AC:

13230

AN:

1110310

Other (OTH)

AF:

0.00961

AC:

579

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

616

1232

1849

2465

3081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00641

AC:

975

AN:

152176

Hom.:

Cov.:

AF XY:

0.00548

AC XY:

408

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41536

American (AMR)

AF:

0.00307

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000831

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00293

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0113

AC:

765

AN:

67980

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

137

182

228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00868

Hom.:

Bravo

AF:

0.00626

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00619

AC:

751

EpiCase

AF:

0.0101

EpiControl

AF:

0.00978

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 26, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chédiak-Higashi syndrome

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LYST: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

LYST-related disorder

Benign:1

Sep 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autoinflammatory syndrome

Benign:1

Jul 20, 2021

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

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.093

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0059

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.4

PhyloP100

5.6

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.18

Sift

Benign

0.17

Sift4G

Uncertain

0.017

Polyphen

0.0010

Vest4

0.18

MVP

0.42

ClinPred

0.030

GERP RS

4.0

Varity_R

0.17

gMVP

0.35

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over