1-235775088-TAA-TA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_000081.4(LYST):c.5461-3del 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 0.027 in 1,036,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.031 (0 hom.)
• Consequence: LYST NM_000081.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-235775088-TA-T is Benign according to our data. Variant chr1-235775088-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 703786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-235775088-TA-T is described in Lovd as [Benign]. Variant chr1-235775088-TA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000308 (45/145980) while in subpopulation AMR AF= 0.000614 (9/14662). AF 95% confidence interval is 0.000319. There are 0 homozygotes in gnomad4. There are 24 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.5461-3del		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.5461-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.000308 AC: 45 AN: 145928 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000614

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000212

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0551 AC: 5336 AN: 96916 Hom.: 0 AF XY: 0.0575 AC XY: 2943 AN XY: 51150

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.0626

Gnomad ASJ exome AF: 0.0591

Gnomad EAS exome AF: 0.0470

Gnomad SAS exome AF: 0.0877

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0314 AC: 27947 AN: 890892 Hom.: 0 Cov.: 27 AF XY: 0.0308 AC XY: 13552 AN XY: 439346

Gnomad4 AFR exome AF: 0.0326

Gnomad4 AMR exome AF: 0.0399

Gnomad4 ASJ exome AF: 0.0334

Gnomad4 EAS exome AF: 0.0235

Gnomad4 SAS exome AF: 0.0350

Gnomad4 FIN exome AF: 0.0321

Gnomad4 NFE exome AF: 0.0310

Gnomad4 OTH exome AF: 0.0305

GnomAD4 genome AF: 0.000308 AC: 45 AN: 145980 Hom.: 0 Cov.: 32 AF XY: 0.000338 AC XY: 24 AN XY: 70992

Gnomad4 AFR AF: 0.000299

Gnomad4 AMR AF: 0.000614

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00112

Gnomad4 NFE AF: 0.000212

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0694 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

Chédiak-Higashi syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 07, 2022	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2019

- -

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: rs557545474; hg19: chr1-235938388;