rs201045270

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP7

The NM_000081.4(LYST):c.8151T>C(p.Ile2717Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000879 in 1,387,256 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

LYST
NM_000081.4 splice_region, synonymous

Scores

Splicing: ADA: 0.1297

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4B:1

Conservation

PhyloP100: 3.25

Publications

0 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 -3 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP7

Synonymous conserved (PhyloP=3.25 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4 link	c.8151T>C	p.Ile2717Ile	splice_region_variant, synonymous_variant	Exon 30 of 53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7 link	c.8151T>C	p.Ile2717Ile	splice_region_variant, synonymous_variant	Exon 30 of 53	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000720

AC:

AN:

249838

AF XY:

0.0000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000850

AC:

105

AN:

1235010

Hom.:

Cov.:

AF XY:

0.0000863

AC XY:

AN XY:

625754

show subpopulations

African (AFR)

AF:

0.0000346

AC:

AN:

28924

American (AMR)

AF:

0.00

AC:

AN:

44334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24752

East Asian (EAS)

AF:

0.00

AC:

AN:

38500

South Asian (SAS)

AF:

0.00

AC:

AN:

81408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3722

European-Non Finnish (NFE)

AF:

0.000108

AC:

AN:

907382

Other (OTH)

AF:

0.000114

AC:

AN:

52706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000112

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41470

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.000105

Hom.:

Bravo

AF:

0.0000604

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Jan 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LYST c.8151T>C (p.Ile2717Ile) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 249838 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.8151T>C in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 211413). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jun 25, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chédiak-Higashi syndrome

Uncertain:1

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 2717 of the LYST mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LYST protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201045270, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 211413). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Oct 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Occurs in the last base pair of the exon Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

LYST-related disorder

Benign:1

Dec 16, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

3.3

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.13

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.020

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