NM_000081.4:c.5023+41C>T

Variant names:

• chr1-235781886-G-A
• rs72763416
• NM_000081.4:c.5023+41C>T

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.954
• Publications: 5 publications found

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]

LYST Gene-Disease associations (from GenCC):

• Chediak-Higashi syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• attenuated Chédiak-Higashi syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.5023+41C>T		intron_variant	Intron 15 of 52	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.5023+41C>T		intron_variant	Intron 15 of 52	5	NM_000081.4	ENSP00000374443.2
LYST	ENST00000489585.5	n.5023+41C>T		intron_variant	Intron 15 of 22	1		ENSP00000513166.1
LYST	ENST00000697178.1	n.*447+41C>T		intron_variant	Intron 14 of 51			ENSP00000513163.1

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

GnomAD2 exomes AF: 0.104 AC: 25707 AN: 246368 AF XY: 0.104

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 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

African (AFR) AF: 0.0709 AC: 1994 AN: 28138

American (AMR) AF: 0.0901 AC: 3989 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3513 AN: 24430

East Asian (EAS) AF: 0.0493 AC: 1893 AN: 38426

South Asian (SAS) AF: 0.0413 AC: 3350 AN: 81050

European-Finnish (FIN) AF: 0.100 AC: 5240 AN: 52294

Middle Eastern (MID) AF: 0.161 AC: 845 AN: 5258

European-Non Finnish (NFE) AF: 0.137 AC: 118438 AN: 866162

Other (OTH) AF: 0.120 AC: 6225 AN: 51692

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

African (AFR) AF: 0.0706 AC: 2928 AN: 41478

American (AMR) AF: 0.106 AC: 1613 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 498 AN: 3472

East Asian (EAS) AF: 0.0434 AC: 225 AN: 5180

South Asian (SAS) AF: 0.0324 AC: 156 AN: 4818

European-Finnish (FIN) AF: 0.101 AC: 1063 AN: 10562

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9343 AN: 67982

Other (OTH) AF: 0.123 AC: 260 AN: 2110

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

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 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

not provided Benign:2

Oct 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.55
DANN	Benign	0.73
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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