rs6665568

Positions:

chr1-235770235-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000081.4(LYST):c.5847G>C(p.Gln1949His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,622 control chromosomes in the GnomAD database, including 1,391 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 765 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 626 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.420

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 Benign. Variant got -19 ACMG points.

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=0.0012516677).

BP6

Variant 1-235770235-C-G is Benign according to our data. Variant chr1-235770235-C-G is described in ClinVar as [Benign]. Clinvar id is 254929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4 linkuse as main transcript	c.5847G>C	p.Gln1949His	missense_variant	20/53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7 linkuse as main transcript	c.5847G>C	p.Gln1949His	missense_variant	20/53	5	NM_000081.4	ENSP00000374443	P1	Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.0542

AC:

8243

AN:

152038

Hom.:

762

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0206

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.0377

GnomAD3 exomes

AF:

0.0143

AC:

3581

AN:

251022

Hom.:

288

AF XY:

0.0106

AC XY:

1436

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.00877

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000741

Gnomad OTH exome

AF:

0.00865

GnomAD4 exome

AF:

0.00570

AC:

8334

AN:

1461466

Hom.:

626

Cov.:

AF XY:

0.00503

AC XY:

3660

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.191

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000486

Gnomad4 OTH exome

AF:

0.0130

GnomAD4 genome

AF:

0.0543

AC:

8269

AN:

152156

Hom.:

765

Cov.:

AF XY:

0.0526

AC XY:

3909

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.188

Gnomad4 AMR

AF:

0.0206

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.0373

Alfa

AF:

0.00885

Hom.:

Bravo

AF:

0.0619

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.188

AC:

828

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0183

AC:

2226

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Chédiak-Higashi syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.066

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.73

MutationTaster

Benign

0.60

P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

0.33

REVEL

Benign

0.093

Sift

Benign

0.37

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.050

MutPred

0.22

Loss of helix (P = 0.0376);

ClinPred

0.00032

GERP RS

0.81

Varity_R

0.056

gMVP

0.36

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

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