1-235800337-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000081.4(LYST):c.3989A>C(p.Asp1330Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,587,506 control chromosomes in the GnomAD database, including 648 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1330G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.037 ( 347 hom., cov: 29)

Exomes 𝑓: 0.0039 ( 301 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.179

Publications

4 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=0.0016427338).

BP6

Variant 1-235800337-T-G is Benign according to our data. Variant chr1-235800337-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	NM_000081.4	MANE Select	c.3989A>C	p.Asp1330Ala	missense	Exon 10 of 53	NP_000072.2
	LYST	NM_001301365.1		c.3989A>C	p.Asp1330Ala	missense	Exon 10 of 53	NP_001288294.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LYST	ENST00000389793.7	TSL:5 MANE Select	c.3989A>C	p.Asp1330Ala	missense	Exon 10 of 53	ENSP00000374443.2
LYST	ENST00000465349.5	TSL:1	n.4540A>C		non_coding_transcript_exon	Exon 10 of 12
LYST	ENST00000489585.5	TSL:1	n.3989A>C		non_coding_transcript_exon	Exon 10 of 23	ENSP00000513166.1

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5619

AN:

151970

Hom.:

346

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0140

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.00991

AC:

2486

AN:

250804

AF XY:

0.00751

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000555

Gnomad OTH exome

AF:

0.00558

GnomAD4 exome

AF:

0.00390

AC:

5598

AN:

1435418

Hom.:

301

Cov.:

AF XY:

0.00335

AC XY:

2400

AN XY:

715734

show subpopulations

African (AFR)

AF:

0.130

AC:

4261

AN:

32820

American (AMR)

AF:

0.00736

AC:

329

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25946

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39502

South Asian (SAS)

AF:

0.000292

AC:

AN:

85670

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00839

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000314

AC:

342

AN:

1088244

Other (OTH)

AF:

0.00987

AC:

587

AN:

59460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

210

420

629

839

1049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.0371

AC:

5639

AN:

152088

Hom.:

347

Cov.:

AF XY:

0.0351

AC XY:

2613

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.129

AC:

5339

AN:

41448

American (AMR)

AF:

0.0140

AC:

213

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68018

Other (OTH)

AF:

0.0218

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

240

479

719

958

1198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0136

Hom.:

239

Bravo

AF:

0.0432

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.117

AC:

515

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0122

AC:

1482

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Chédiak-Higashi syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jul 14, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autoinflammatory syndrome

Benign:1

Feb 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.036

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.014

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.4

PhyloP100

0.18

PrimateAI

Benign

0.27

PROVEAN

Benign

0.96

REVEL

Benign

0.11

Sift

Benign

0.84

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.10

MPC

0.096

ClinPred

0.0026

GERP RS

4.6

Varity_R

0.044

gMVP

0.095

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over