rs6696123

chr1-235781994-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000081.4(LYST):c.4956A>G(p.Leu1652=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,611,766 control chromosomes in the GnomAD database, including 124,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13168 hom., cov: 31)
  • Exomes 𝑓: 0.38 (111053 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.385

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-235781994-T-C is Benign according to our data. Variant chr1-235781994-T-C is described in ClinVar as [Benign]. Clinvar id is 254923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.385 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.4956A>G	p.Leu1652=	synonymous_variant	15/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.4956A>G	p.Leu1652=	synonymous_variant	15/53	5	NM_000081.4	P1
LYST	ENST00000489585.5	c.4956A>G	p.Leu1652=	synonymous_variant, NMD_transcript_variant	15/23	1
LYST	ENST00000697178.1	c.*380A>G		3_prime_UTR_variant, NMD_transcript_variant	14/52

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61498 AN: 151856 Hom.: 13154 Cov.: 31

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.345 AC: 86470 AN: 250828 Hom.: 16516 AF XY: 0.339 AC XY: 45981 AN XY: 135574

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.0588

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.382 AC: 557670 AN: 1459794 Hom.: 111053 Cov.: 34 AF XY: 0.377 AC XY: 273600 AN XY: 726288

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.368

Gnomad4 EAS exome AF: 0.0856

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.434

Gnomad4 NFE exome AF: 0.405

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.405 AC: 61559 AN: 151972 Hom.: 13168 Cov.: 31 AF XY: 0.398 AC XY: 29552 AN XY: 74266

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.0632

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.408

Gnomad4 OTH AF: 0.389

Alfa AF: 0.398 Hom.: 28389

Bravo AF: 0.401

Asia WGS AF: 0.156 AC: 544 AN: 3478

EpiCase AF: 0.391

EpiControl AF: 0.399

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: MAF -

Chédiak-Higashi syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.6
Dann	Benign	0.67

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: rs6696123; hg19: chr1-235945294; COSMIC: COSV67705068;