rs146591126

chr1-235766255-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000081.4(LYST):c.5945C>T(p.Thr1982Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00949 in 1,610,604 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (76 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.56

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LYST
• BP4: Computational evidence support a benign effect (MetaRNN=0.0058999956).
• BP6: Variant 1-235766255-G-A is Benign according to our data. Variant chr1-235766255-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00641 (975/152176) while in subpopulation NFE AF= 0.0113 (765/67980). AF 95% confidence interval is 0.0106. There are 7 homozygotes in gnomad4. There are 408 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.5945C>T	p.Thr1982Ile	missense_variant	21/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.5945C>T	p.Thr1982Ile	missense_variant	21/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 975 AN: 152058 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00597 AC: 1480 AN: 247718 Hom.: 4 AF XY: 0.00591 AC XY: 793 AN XY: 134200

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00192

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000567

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00615

GnomAD4 exome AF: 0.00981 AC: 14303 AN: 1458428 Hom.: 76 Cov.: 31 AF XY: 0.00955 AC XY: 6930 AN XY: 725596

Gnomad4 AFR exome AF: 0.00150

Gnomad4 AMR exome AF: 0.00310

Gnomad4 ASJ exome AF: 0.00219

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000665

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00961

GnomAD4 genome AF: 0.00641 AC: 975 AN: 152176 Hom.: 7 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74404

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00293

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00919 Hom.: 12

Bravo AF: 0.00626

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.00619 AC: 751

EpiCase AF: 0.0101

EpiControl AF: 0.00978

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2015	- -

Chédiak-Higashi syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 24, 2021	- -

LYST-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

LYST: BP4, BS1, BS2 -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.57	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.18
Sift	Benign	0.17	T
Sift4G	Uncertain	0.017	D
Polyphen		0.0010	B
Vest4		0.18
MVP		0.42
ClinPred		0.030	T
GERP RS		4.0
Varity_R		0.17
gMVP		0.35

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: rs146591126; hg19: chr1-235929555; COSMIC: COSV101089911;