1-235663082-TAAAA-TAAA

Variant names:

• chr1-235663082-TA-T
• rs36014994
• NM_000081.4:c.11268-5delT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000081.4(LYST):​c.11268-5delT variant causes a splice region, 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24874 hom., cov: 0)
  • Exomes 𝑓: 0.45 (44544 hom.)
  • Failed GnomAD Quality Control
• Consequence: LYST NM_000081.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• 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 Benign. Variant got -16 ACMG points.

• BP6: Variant 1-235663082-TA-T is Benign according to our data. Variant chr1-235663082-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 403065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-235663082-TA-T is described in Lovd as [Benign]. Variant chr1-235663082-TA-T is described in Lovd as [Likely_benign]. Variant chr1-235663082-TA-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.11268-5delT		splice_region_variant, intron_variant	Intron 52 of 52	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.11268-5delT		splice_region_variant, intron_variant	Intron 52 of 52	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.553 AC: 82566 AN: 149220 Hom.: 24831 Cov.: 0

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.0495

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.525

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.451 AC: 505703 AN: 1122018 Hom.: 44544 Cov.: 0 AF XY: 0.451 AC XY: 251328 AN XY: 557718

Gnomad4 AFR exome AF: 0.582

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.469

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.462

Gnomad4 OTH exome AF: 0.449

GnomAD4 genome AF: 0.554 AC: 82650 AN: 149304 Hom.: 24874 Cov.: 0 AF XY: 0.540 AC XY: 39239 AN XY: 72718

Gnomad4 AFR AF: 0.774

Gnomad4 AMR AF: 0.390

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.0497

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.549

Gnomad4 NFE AF: 0.526

Gnomad4 OTH AF: 0.522

Bravo AF: 0.553

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chédiak-Higashi syndrome Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

African/African American population allele frequency is 66.84% (rs767372373, 14,577/20,186 alleles, 4,812 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.1.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

Jun 11, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported. -

not provided Benign:2 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27781387, 29357941) -

Autoinflammatory syndrome Benign:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;