1-235775088-TAA-TAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000081.4(LYST):c.5461-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,114,534 control chromosomes in the GnomAD database, including 45 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 32)

Exomes 𝑓: 0.044 ( 26 hom. )

Consequence

LYST
NM_000081.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.462

Publications

2 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 -9 ACMG points.

BP6

Variant 1-235775088-T-TA is Benign according to our data. Variant chr1-235775088-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211409.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0111 (1627/146228) while in subpopulation SAS AF = 0.0197 (92/4660). AF 95% confidence interval is 0.0165. There are 19 homozygotes in GnomAd4. There are 817 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4 link	c.5461-3dupT		splice_region_variant, intron_variant	Intron 17 of 52	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.5461-3_5461-2insT		splice_region_variant, intron_variant	Intron 17 of 52	5	NM_000081.4	ENSP00000374443.2		Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1626

AN:

146176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00284

Gnomad AMI

AF:

0.00552

Gnomad AMR

AF:

0.0182

Gnomad ASJ

AF:

0.00678

Gnomad EAS

AF:

0.000983

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.00906

GnomAD2 exomes

AF:

0.0521

AC:

5054

AN:

96916

AF XY:

0.0521

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.0419

Gnomad EAS exome

AF:

0.0125

Gnomad FIN exome

AF:

0.0522

Gnomad NFE exome

AF:

0.0426

Gnomad OTH exome

AF:

0.0507

GnomAD4 exome

AF:

0.0438

AC:

42404

AN:

968306

Hom.:

Cov.:

AF XY:

0.0428

AC XY:

20542

AN XY:

480436

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0266

AC:

578

AN:

21702

American (AMR)

AF:

0.0645

AC:

1878

AN:

29114

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

486

AN:

16072

East Asian (EAS)

AF:

0.0139

AC:

333

AN:

23938

South Asian (SAS)

AF:

0.0437

AC:

2466

AN:

56378

European-Finnish (FIN)

AF:

0.0344

AC:

1150

AN:

33470

Middle Eastern (MID)

AF:

0.0281

AC:

115

AN:

4088

European-Non Finnish (NFE)

AF:

0.0454

AC:

33787

AN:

744488

Other (OTH)

AF:

0.0412

AC:

1611

AN:

39056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.328

Heterozygous variant carriers

3640

7280

10919

14559

18199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1472

2944

4416

5888

7360

<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:

0.0111

AC:

1627

AN:

146228

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

817

AN XY:

71144

show subpopulations

African (AFR)

AF:

0.00283

AC:

114

AN:

40228

American (AMR)

AF:

0.0182

AC:

268

AN:

14688

Ashkenazi Jewish (ASJ)

AF:

0.00678

AC:

AN:

3390

East Asian (EAS)

AF:

0.000986

AC:

AN:

5072

South Asian (SAS)

AF:

0.0197

AC:

AN:

4660

European-Finnish (FIN)

AF:

0.0168

AC:

151

AN:

8988

Middle Eastern (MID)

AF:

0.00709

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0144

AC:

949

AN:

66008

Other (OTH)

AF:

0.00897

AC:

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0349

Hom.:

Bravo

AF:

0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 16, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2016

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autoinflammatory syndrome

Uncertain:1

May 16, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chédiak-Higashi syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.46

Mutation Taster

=94/6

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over