rs41308172

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000081.4(LYST):​c.10800+4G>T variant causes a splice donor 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: đť‘“ 0.0045 ( 6 hom., cov: 32)
Exomes đť‘“: 0.0067 ( 44 hom. )

Consequence

LYST
NM_000081.4 splice_donor_region, intron

Scores

2
Splicing: ADA: 0.009497
2

Clinical Significance

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

Conservation

PhyloP100: 0.384
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 Benign. Variant got -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 id is 296350.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}. Variant chr1-235686945-C-A is described in Lovd as [Benign]. Variant chr1-235686945-C-A is described in Lovd as [Likely_benign].
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LYSTNM_000081.4 linkuse as main transcriptc.10800+4G>T splice_donor_region_variant, intron_variant ENST00000389793.7 NP_000072.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LYSTENST00000389793.7 linkuse as main transcriptc.10800+4G>T splice_donor_region_variant, intron_variant 5 NM_000081.4 ENSP00000374443 P1Q99698-1

Frequencies

GnomAD3 genomes
AF:
0.00451
AC:
686
AN:
152210
Hom.:
6
Cov.:
32
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
GnomAD3 exomes
AF:
0.00643
AC:
1618
AN:
251454
Hom.:
11
AF XY:
0.00617
AC XY:
838
AN XY:
135902
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 SAS exome
AF:
0.00405
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.:
44
Cov.:
30
AF XY:
0.00665
AC XY:
4829
AN XY:
726498
show subpopulations
Gnomad4 AFR exome
AF:
0.000957
Gnomad4 AMR exome
AF:
0.0167
Gnomad4 ASJ exome
AF:
0.00188
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00458
Gnomad4 FIN exome
AF:
0.000880
Gnomad4 NFE exome
AF:
0.00732
Gnomad4 OTH exome
AF:
0.00578
GnomAD4 genome
AF:
0.00449
AC:
684
AN:
152328
Hom.:
6
Cov.:
32
AF XY:
0.00412
AC XY:
307
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.00149
Gnomad4 AMR
AF:
0.00680
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00476
Gnomad4 FIN
AF:
0.000848
Gnomad4 NFE
AF:
0.00681
Gnomad4 OTH
AF:
0.00710
Alfa
AF:
0.00655
Hom.:
3
Bravo
AF:
0.00550
Asia WGS
AF:
0.00144
AC:
5
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
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 09, 2014- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024LYST: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 25, 2021- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 03, 2015- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Autoinflammatory syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJan 28, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.20
CADD
Benign
18
DANN
Benign
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0095
dbscSNV1_RF
Benign
0.082
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

LitVar

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

Other links and lift over

dbSNP: rs41308172; hg19: chr1-235850245; API