rs147221131

Positions:

chr1-235664574-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP6BS1

The NM_000081.4(LYST):c.11086G>A(p.Val3696Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3696A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.27

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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.

BP6

Variant 1-235664574-C-T is Benign according to our data. Variant chr1-235664574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr1-235664574-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000552 (84/152274) while in subpopulation NFE AF= 0.000955 (65/68030). AF 95% confidence interval is 0.000768. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4 linkuse as main transcript	c.11086G>A	p.Val3696Ile	missense_variant	51/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7 linkuse as main transcript	c.11086G>A	p.Val3696Ile	missense_variant	51/53	5	NM_000081.4	P1	Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000605

AC:

152

AN:

251038

Hom.:

AF XY:

0.000575

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000644

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.000697

AC:

1019

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000642

AC XY:

467

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000795

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000552

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000955

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000780

Hom.:

Bravo

AF:

0.000650

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000749

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chédiak-Higashi syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2019	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LYST: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in a proband with a fatal case of H1N1 influenza and in at least one individual from a cohort of patients with primary lateral sclerosis, but familial segregation information and further clinical information were not provided (PMID: 31325016, 26597256); This variant is associated with the following publications: (PMID: 26597256, Cheung2021[preprint], 31325016) -

LYST-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2023

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

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 03, 2023

Variant summary: LYST c.11086G>A (p.Val3696Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251038 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.52 fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.11086G>A in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as a avriant of uncertain significance, while one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

Eigen

Benign

-0.051

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.0048

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.88

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.51

REVEL

Benign

0.097

Sift

Benign

0.26

Sift4G

Benign

0.70

Polyphen

0.64

Vest4

0.19

MVP

0.41

ClinPred

0.018

GERP RS

5.0

Varity_R

0.041

gMVP

0.054

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.36

Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over