chr1-235809154-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS1

The NM_000081.4(LYST):c.1664A>C(p.His555Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.48

Publications

6 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: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.39767122).

BP6

Variant 1-235809154-T-G is Benign according to our data. Variant chr1-235809154-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572466.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000118 (18/152312) while in subpopulation AMR AF = 0.00111 (17/15290). AF 95% confidence interval is 0.000708. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1664A>C	p.His555Pro	missense	Exon 5 of 53	NP_000072.2
	LYST	NM_001301365.1		c.1664A>C	p.His555Pro	missense	Exon 5 of 53	NP_001288294.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LYST	ENST00000389793.7	TSL:5 MANE Select	c.1664A>C	p.His555Pro	missense	Exon 5 of 53	ENSP00000374443.2
LYST	ENST00000465349.5	TSL:1	n.2215A>C		non_coding_transcript_exon	Exon 5 of 12
LYST	ENST00000489585.5	TSL:1	n.1664A>C		non_coding_transcript_exon	Exon 5 of 23	ENSP00000513166.1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000267

AC:

AN:

250822

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.00157

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111908

Other (OTH)

AF:

0.0000828

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000118

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.00111

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000499

Hom.:

Bravo

AF:

0.000340

ExAC

AF:

0.000198

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Chédiak-Higashi syndrome (3)

LYST-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.0034

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.064

MetaRNN

Benign

0.40

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

2.0

PhyloP100

7.5

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.60

Sift

Benign

0.055

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MVP

0.81

MPC

0.55

ClinPred

0.19

GERP RS

5.6

Varity_R

0.76

gMVP

0.78

Mutation Taster

=48/52

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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