NM_000081.4:c.11268-5dupT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_000081.4(LYST):c.11268-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.00026 ( 0 hom., cov: 0)

Exomes 𝑓: 0.017 ( 0 hom. )

Consequence

LYST
NM_000081.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.694

Publications

6 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 1-235663082-T-TA is Benign according to our data. Variant chr1-235663082-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296343.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000261 (39/149444) while in subpopulation EAS AF = 0.00237 (12/5056). AF 95% confidence interval is 0.00137. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4 link	c.11268-5dupT		splice_region_variant, intron_variant	Intron 52 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.11268-5_11268-4insT		splice_region_variant, intron_variant	Intron 52 of 52	5	NM_000081.4	ENSP00000374443.2		Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.000261

AC:

AN:

149358

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000471

Gnomad ASJ

AF:

0.000291

Gnomad EAS

AF:

0.00237

Gnomad SAS

AF:

0.000851

Gnomad FIN

AF:

0.000404

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000164

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00771

AC:

1258

AN:

163066

AF XY:

0.00766

show subpopulations

Gnomad AFR exome

AF:

0.000427

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.00415

Gnomad EAS exome

AF:

0.0305

Gnomad FIN exome

AF:

0.00753

Gnomad NFE exome

AF:

0.00362

Gnomad OTH exome

AF:

0.00696

GnomAD4 exome

AF:

0.0168

AC:

19516

AN:

1163230

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

9447

AN XY:

582630

show subpopulations

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

African (AFR)

AF:

0.00296

AC:

AN:

25706

American (AMR)

AF:

0.0143

AC:

518

AN:

36112

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

240

AN:

21864

East Asian (EAS)

AF:

0.0462

AC:

1263

AN:

27314

South Asian (SAS)

AF:

0.0193

AC:

1308

AN:

67612

European-Finnish (FIN)

AF:

0.00839

AC:

381

AN:

45434

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

4706

European-Non Finnish (NFE)

AF:

0.0168

AC:

14864

AN:

885494

Other (OTH)

AF:

0.0166

AC:

815

AN:

48988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.264

Heterozygous variant carriers

2226

4452

6677

8903

11129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

714

1428

2142

2856

3570

<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:

0.000261

AC:

AN:

149444

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

AN XY:

72798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41042

American (AMR)

AF:

0.000470

AC:

AN:

14888

Ashkenazi Jewish (ASJ)

AF:

0.000291

AC:

AN:

3432

East Asian (EAS)

AF:

0.00237

AC:

AN:

5056

South Asian (SAS)

AF:

0.000854

AC:

AN:

4684

European-Finnish (FIN)

AF:

0.000404

AC:

AN:

9910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000164

AC:

AN:

67170

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0182

Hom.:

1207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chédiak-Higashi syndrome

Uncertain:1Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Aug 01, 2018

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

PhyloP100

-0.69

Mutation Taster

=99/1

polymorphism

(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

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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