rs41308172

Positions:

• chr1-235686945-C-A
• chr1-235686945-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000081.4(LYST):​c.10800+4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,612,438 control chromosomes in the GnomAD database, including 50 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (44 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Scores: Splicing: ADA: 0.009497
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.384

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 (HGNC:):

ACMG classification

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, Uncertain_significance=1, Benign=2}. 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
LYST	NM_000081.4	c.10800+4G>T		splice_region_variant, intron_variant		ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.10800+4G>T		splice_region_variant, intron_variant		5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152210 Hom.: 6 Cov.: 32

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

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

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

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:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LYST: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2021	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 03, 2015	- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 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

Other links and lift over

dbSNP: rs41308172; hg19: chr1-235850245;