rs2753327

Positions:

• chr1-235731173-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4_Strong BS1_Supporting

The NM_000081.4(LYST):​c.8806G>A​(p.Val2936Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000889 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V2936V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 3.89

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LYST. . Trascript score misZ 4.0845 (greater than threshold 3.09). GenCC has associacion of gene with Chediak-Higashi syndrome, attenuated Chédiak-Higashi syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.041005164).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000525 (80/152256) while in subpopulation NFE AF= 0.000838 (57/68018). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4	c.8806G>A	p.Val2936Ile	missense_variant	35/53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.8806G>A	p.Val2936Ile	missense_variant	35/53	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000581 AC: 146 AN: 251388 Hom.: 0 AF XY: 0.000567 AC XY: 77 AN XY: 135864

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000927 AC: 1355 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.000857 AC XY: 623 AN XY: 727182

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152256 Hom.: 0 Cov.: 31 AF XY: 0.000430 AC XY: 32 AN XY: 74442

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000892 Hom.: 0

Bravo AF: 0.000536

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	May 11, 2021	LYST NM_000081.3 exon 35 p.Val2936Ile (c.8806G>A): This variant has not been reported in the literature but is present in 0.08% (57/68026) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235731173-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:525145). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 05, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2936 of the LYST protein (p.Val2936Ile). This variant is present in population databases (rs2753327, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 525145). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LYST protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2023	Observed in a patient with primary platelet secretion defect; this individual also harbored variants in other possible causative genes (Gorski et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30819905, 18485661, 27535533) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	LYST: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 08, 2024	BS1, BP4 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2021

(Gorski, 2019; Leinoe, 2017) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.061
Sift	Benign	0.30	T
Sift4G	Uncertain	0.035	D
Polyphen		0.023	B
Vest4		0.24
MVP		0.43
ClinPred		0.017	T
GERP RS		3.7
Varity_R		0.057
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2753327; hg19: chr1-235894473;