rs6665568

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1949Q) has been classified as Likely 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

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

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

LYST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	NM_000081.4	MANE Select	c.5847G>C	p.Gln1949His	missense	Exon 20 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.5847G>C	p.Gln1949His	missense	Exon 20 of 53	NP_001288294.1	Q99698-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LYST	ENST00000389793.7	TSL:5 MANE Select	c.5847G>C	p.Gln1949His	missense	Exon 20 of 53	ENSP00000374443.2	Q99698-1
LYST	ENST00000489585.5	TSL:1	n.5847G>C		non_coding_transcript_exon	Exon 20 of 23	ENSP00000513166.1	Q99698-2
LYST	ENST00000697241.1		c.279G>C	p.Gln93His	missense	Exon 3 of 26	ENSP00000513206.1	A0A8V8TM69

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

GnomAD2 exomes

AF:

0.0143

AC:

3581

AN:

251022

AF XY:

0.0106

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 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

African (AFR)

AF:

0.191

AC:

6398

AN:

33450

American (AMR)

AF:

0.0104

AC:

463

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.000417

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000486

AC:

540

AN:

1111720

Other (OTH)

AF:

0.0130

AC:

785

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

378

756

1135

1513

1891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0543

AC:

8269

AN:

152156

Hom.:

765

Cov.:

AF XY:

0.0526

AC XY:

3909

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.188

AC:

7809

AN:

41484

American (AMR)

AF:

0.0206

AC:

314

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

67990

Other (OTH)

AF:

0.0373

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

351

703

1054

1406

1757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Chédiak-Higashi syndrome (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

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

PhyloP100

-0.42

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

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over