rs41308172

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000081.4(LYST):c.10800+4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,612,438 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.0045 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 44 hom. )

Consequence

LYST
NM_000081.4 splice_region, intron

Scores

Splicing: ADA: 0.009497

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.384

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:

ENSG00000296841 (HGNC:):

ENSG00000296841 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.2).

BP6

Variant 1-235686945-C-A is Benign according to our data. Variant chr1-235686945-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296350.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00449 (684/152328) while in subpopulation NFE AF = 0.00681 (463/68026). AF 95% confidence interval is 0.00629. There are 6 homozygotes in GnomAd4. There are 307 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4 link	c.10800+4G>T		splice_region_variant, intron_variant	Intron 48 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.10800+4G>T		splice_region_variant, intron_variant	Intron 48 of 52	5	NM_000081.4	ENSP00000374443.2		Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

686

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00681

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00643

AC:

1618

AN:

251454

AF XY:

0.00617

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00676

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00669

AC:

9763

AN:

1460110

Hom.:

Cov.:

AF XY:

0.00665

AC XY:

4829

AN XY:

726498

show subpopulations

African (AFR)

AF:

0.000957

AC:

AN:

33444

American (AMR)

AF:

0.0167

AC:

745

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39668

South Asian (SAS)

AF:

0.00458

AC:

395

AN:

86226

European-Finnish (FIN)

AF:

0.000880

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00732

AC:

8126

AN:

1110418

Other (OTH)

AF:

0.00578

AC:

349

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

445

890

1334

1779

2224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.00449

AC:

684

AN:

152328

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

307

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41574

American (AMR)

AF:

0.00680

AC:

104

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00476

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00681

AC:

463

AN:

68026

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00658

Hom.:

Bravo

AF:

0.00550

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00573

EpiControl

AF:

0.00699

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chédiak-Higashi syndrome

Uncertain:1Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LYST: BP4, BS1, BS2 -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 25, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 03, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Jan 28, 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

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.38

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0095

dbscSNV1_RF

Benign

0.082

Splicevardb

2.0

SpliceAI score (max)

0.030

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