1-235775088-TAA-TAAA

Position:

• chr1-235775088-TAA-TAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000081.4(LYST):​c.5461-3_5461-2insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,114,534 control chromosomes in the GnomAD database, including 45 homozygotes. 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 0.011 (19 hom., cov: 32)
  • Exomes 𝑓: 0.044 (26 hom.)
• Consequence: LYST NM_000081.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.462

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 1-235775088-T-TA is Benign according to our data. Variant chr1-235775088-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211409.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=2}.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4	c.5461-3_5461-2insT		splice_region_variant, splice_polypyrimidine_tract_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.5461-3_5461-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000081.4	ENSP00000374443	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1626 AN: 146176 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00284

Gnomad AMI AF: 0.00552

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.00678

Gnomad EAS AF: 0.000983

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00906

GnomAD3 exomes AF: 0.0521 AC: 5054 AN: 96916 Hom.: 7 AF XY: 0.0521 AC XY: 2663 AN XY: 51150

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.0125

Gnomad SAS exome AF: 0.0702

Gnomad FIN exome AF: 0.0522

Gnomad NFE exome AF: 0.0426

Gnomad OTH exome AF: 0.0507

GnomAD4 exome AF: 0.0438 AC: 42404 AN: 968306 Hom.: 26 Cov.: 27 AF XY: 0.0428 AC XY: 20542 AN XY: 480436

Gnomad4 AFR exome AF: 0.0266

Gnomad4 AMR exome AF: 0.0645

Gnomad4 ASJ exome AF: 0.0302

Gnomad4 EAS exome AF: 0.0139

Gnomad4 SAS exome AF: 0.0437

Gnomad4 FIN exome AF: 0.0344

Gnomad4 NFE exome AF: 0.0454

Gnomad4 OTH exome AF: 0.0412

GnomAD4 genome AF: 0.0111 AC: 1627 AN: 146228 Hom.: 19 Cov.: 32 AF XY: 0.0115 AC XY: 817 AN XY: 71144

Gnomad4 AFR AF: 0.00283

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.00678

Gnomad4 EAS AF: 0.000986

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.0168

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.00897

Bravo AF: 0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 16, 2017

- -

Chédiak-Higashi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs557545474; hg19: chr1-235938388;