1-235775088-TAA-TAAAA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_000081.4(LYST):c.5461-3_5461-2insTT 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 0.000307 in 1,262,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: LYST NM_000081.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• 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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-235775088-T-TAA is Benign according to our data. Variant chr1-235775088-T-TAA is described in ClinVar as [Benign]. Clinvar id is 1167294.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000396 (58/146282) while in subpopulation EAS AF= 0.00355 (18/5072). AF 95% confidence interval is 0.00229. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000397 AC: 58 AN: 146230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00354

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00112 AC: 109 AN: 96916 Hom.: 0 AF XY: 0.00102 AC XY: 52 AN XY: 51150

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0125

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000119

Gnomad NFE exome AF: 0.0000639

Gnomad OTH exome AF: 0.000448

GnomAD4 exome AF: 0.000296 AC: 330 AN: 1116394 Hom.: 0 Cov.: 27 AF XY: 0.000270 AC XY: 150 AN XY: 556488

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.0000884

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00635

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.0000261

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.000219

GnomAD4 genome AF: 0.000396 AC: 58 AN: 146282 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 22 AN XY: 71174

Gnomad4 AFR AF: 0.000870

Gnomad4 AMR AF: 0.000272

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00355

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000151

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000559

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Chédiak-Higashi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 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

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;