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rs145298434

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000081.4(LYST):c.1829A>T(p.His610Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000205 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

3
2
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.83
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, LYST
BP4
Computational evidence support a benign effect (MetaRNN=0.09874347).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LYSTNM_000081.4 linkuse as main transcriptc.1829A>T p.His610Leu missense_variant 5/53 ENST00000389793.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LYSTENST00000389793.7 linkuse as main transcriptc.1829A>T p.His610Leu missense_variant 5/535 NM_000081.4 P1Q99698-1

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000279
AC:
70
AN:
250588
Hom.:
0
AF XY:
0.000243
AC XY:
33
AN XY:
135646
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00171
Gnomad NFE exome
AF:
0.000185
Gnomad OTH exome
AF:
0.00115
GnomAD4 exome
AF:
0.000207
AC:
302
AN:
1461784
Hom.:
0
Cov.:
35
AF XY:
0.000206
AC XY:
150
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00217
Gnomad4 NFE exome
AF:
0.000151
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000191
AC:
29
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000942
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000124
Hom.:
0
Bravo
AF:
0.000121
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000255
AC:
31
EpiCase
AF:
0.000109
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoNov 09, 2022This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.09% [10/10620]; https://gnomad.broadinstitute.org/variant/1-235808989-T-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 454482). Evolutionary conservation and computational prediction 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 submitterclinical testingInvitaeNov 01, 2022This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 610 of the LYST protein (p.His610Leu). This variant is present in population databases (rs145298434, gnomAD 0.2%). 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: 454482). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.17
Cadd
Benign
22
Dann
Benign
0.96
DEOGEN2
Uncertain
0.51
D;.
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.84
T;T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.099
T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
1.7
L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Benign
0.20
Sift
Benign
0.085
T;T
Sift4G
Pathogenic
0.0010
D;D
Polyphen
0.72
P;.
Vest4
0.67
MVP
0.60
MPC
0.11
ClinPred
0.069
T
GERP RS
4.5
Varity_R
0.42
gMVP
0.69

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.

Other links and lift over

dbSNP: rs145298434; hg19: chr1-235972289; API