rs201045270

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_000081.4(LYST):​c.8151T>C​(p.Ile2717=) 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

2
Splicing: ADA: 0.1297
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1

Conservation

PhyloP100: 3.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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/exons MANE Protein UniProt
LYSTNM_000081.4 linkuse as main transcriptc.8151T>C p.Ile2717= splice_region_variant, synonymous_variant 30/53 ENST00000389793.7 NP_000072.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LYSTENST00000389793.7 linkuse as main transcriptc.8151T>C p.Ile2717= splice_region_variant, synonymous_variant 30/535 NM_000081.4 ENSP00000374443 P1Q99698-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152246
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000720
AC:
18
AN:
249838
Hom.:
0
AF XY:
0.0000739
AC XY:
10
AN XY:
135408
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 SAS 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.:
0
Cov.:
20
AF XY:
0.0000863
AC XY:
54
AN XY:
625754
show subpopulations
Gnomad4 AFR exome
AF:
0.0000346
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000108
Gnomad4 OTH exome
AF:
0.000114
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152246
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000105
Hom.:
0
Bravo
AF:
0.0000604
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 25, 2015- -
Chédiak-Higashi syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 25, 2022This 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 16, 2021Occurs 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
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 16, 2023This 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
13
DANN
Benign
0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201045270; hg19: chr1-235907279; API