Genetic Variant LYST:c.11268-6_11268-5delTT (chr1-235663082-TAA-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000081.4(LYST):c.11268-6_11268-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,314,560 control chromosomes in the GnomAD database, including 22 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 14 hom., cov: 0)

Exomes 𝑓: 0.012 ( 8 hom. )

Consequence

LYST
NM_000081.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.14

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: Benign. The variant received -16 ACMG points.

BP6

Variant 1-235663082-TAA-T is Benign according to our data. Variant chr1-235663082-TAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00552 (824/149400) while in subpopulation AFR AF = 0.0174 (715/41034). AF 95% confidence interval is 0.0164. There are 14 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4 link	c.11268-6_11268-5delTT		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.11268-6_11268-5delTT		splice_region_variant, intron_variant	Intron 52 of 52	5	NM_000081.4	ENSP00000374443.2		Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.00551

AC:

822

AN:

149314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.000583

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.000909

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000268

Gnomad OTH

AF:

0.00388

GnomAD2 exomes

AF:

0.00691

AC:

1127

AN:

163066

AF XY:

0.00603

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.00672

Gnomad ASJ exome

AF:

0.00608

Gnomad EAS exome

AF:

0.000275

Gnomad FIN exome

AF:

0.00834

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.00936

GnomAD4 exome

AF:

0.0117

AC:

13682

AN:

1165160

Hom.:

AF XY:

0.0109

AC XY:

6373

AN XY:

585776

show subpopulations

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

African (AFR)

AF:

0.0506

AC:

1168

AN:

23076

American (AMR)

AF:

0.00503

AC:

195

AN:

38730

Ashkenazi Jewish (ASJ)

AF:

0.00823

AC:

178

AN:

21628

East Asian (EAS)

AF:

0.000180

AC:

AN:

33368

South Asian (SAS)

AF:

0.000977

AC:

AN:

76802

European-Finnish (FIN)

AF:

0.00876

AC:

386

AN:

44070

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

4692

European-Non Finnish (NFE)

AF:

0.0127

AC:

11084

AN:

873794

Other (OTH)

AF:

0.0110

AC:

538

AN:

49000

⚠️ 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: 0.272

Heterozygous variant carriers

1617

3233

4850

6466

8083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

516

1032

1548

2064

2580

<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:

0.00552

AC:

824

AN:

149400

Hom.:

Cov.:

AF XY:

0.00558

AC XY:

406

AN XY:

72770

show subpopulations

African (AFR)

AF:

0.0174

AC:

715

AN:

41034

American (AMR)

AF:

0.00477

AC:

AN:

14890

Ashkenazi Jewish (ASJ)

AF:

0.000583

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

5058

South Asian (SAS)

AF:

0.000213

AC:

AN:

4684

European-Finnish (FIN)

AF:

0.000909

AC:

AN:

9896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000268

AC:

AN:

67142

Other (OTH)

AF:

0.00385

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

119

159

199

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:

0.0237

Hom.:

1207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 13, 2019

GeneDx

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

1.1

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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1-235663082-TAAAA-TAA

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