rs72763416

Positions:

• chr1-235781886-G-A
• chr1-235781886-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000081.4(LYST):​c.5023+41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,343,810 control chromosomes in the GnomAD database, including 10,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (969 hom., cov: 32)
  • Exomes 𝑓: 0.12 (9528 hom.)
• Consequence: LYST NM_000081.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.954

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-235781886-G-A is Benign according to our data. Variant chr1-235781886-G-A is described in ClinVar as [Benign]. Clinvar id is 254924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.5023+41C>T		intron_variant		ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.5023+41C>T		intron_variant		5	NM_000081.4	P1
LYST	ENST00000489585.5	c.5023+41C>T		intron_variant, NMD_transcript_variant		1
LYST	ENST00000697178.1	c.*447+41C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16254 AN: 151952 Hom.: 971 Cov.: 32

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.104 AC: 25707 AN: 246368 Hom.: 1481 AF XY: 0.104 AC XY: 13877 AN XY: 133434

Gnomad AFR exome AF: 0.0709

Gnomad AMR exome AF: 0.0880

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0493

Gnomad SAS exome AF: 0.0408

Gnomad FIN exome AF: 0.0966

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.122 AC: 145487 AN: 1191738 Hom.: 9528 Cov.: 17 AF XY: 0.120 AC XY: 72795 AN XY: 605286

Gnomad4 AFR exome AF: 0.0709

Gnomad4 AMR exome AF: 0.0901

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0493

Gnomad4 SAS exome AF: 0.0413

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.107 AC: 16250 AN: 152072 Hom.: 969 Cov.: 32 AF XY: 0.103 AC XY: 7645 AN XY: 74352

Gnomad4 AFR AF: 0.0706

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.0434

Gnomad4 SAS AF: 0.0324

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.123

Alfa AF: 0.124 Hom.: 230

Bravo AF: 0.108

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.55
DANN	Benign	0.73

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: rs72763416; hg19: chr1-235945186; COSMIC: COSV67705060;