1-235663082-TAAA-TAAAA

Position:

• chr1-235663082-TAAA-TAAAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_000081.4(LYST):​c.11268-5_11268-4insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 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 0.00026 (0 hom., cov: 0)
  • Exomes 𝑓: 0.017 (0 hom.)
• Consequence: LYST NM_000081.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.694

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 1-235663082-T-TA is Benign according to our data. Variant chr1-235663082-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296343.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000261 (39/149444) while in subpopulation EAS AF= 0.00237 (12/5056). AF 95% confidence interval is 0.00137. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.11268-5_11268-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.11268-5_11268-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.000261 AC: 39 AN: 149358 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000471

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00237

Gnomad SAS AF: 0.000851

Gnomad FIN AF: 0.000404

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0168 AC: 19516 AN: 1163230 Hom.: 0 Cov.: 0 AF XY: 0.0162 AC XY: 9447 AN XY: 582630

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.0462

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.00839

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.000261 AC: 39 AN: 149444 Hom.: 0 Cov.: 0 AF XY: 0.000220 AC XY: 16 AN XY: 72798

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000470

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.00237

Gnomad4 SAS AF: 0.000854

Gnomad4 FIN AF: 0.000404

Gnomad4 NFE AF: 0.000164

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs36014994; hg19: chr1-235826382;