rs187257944

Positions:

chr1-235806656-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_000081.4(LYST):c.2480T>A(p.Leu827Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.17

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4 linkuse as main transcript	c.2480T>A	p.Leu827Gln	missense_variant	6/53	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.2480T>A	p.Leu827Gln	missense_variant	6/53	5	NM_000081.4	ENSP00000374443	P1	Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251236

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461632

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000112

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Chédiak-Higashi syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 827 of the LYST protein (p.Leu827Gln). This variant is present in population databases (rs187257944, gnomAD 0.01%). 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: 579001). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 07, 2024

Variant summary: LYST c.2480T>A (p.Leu827Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251236 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (6e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2480T>A in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 579001). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.2480T>A (p.L827Q) alteration is located in exon 6 (coding exon 4) of the LYST gene. This alteration results from a T to A substitution at nucleotide position 2480, causing the leucine (L) at amino acid position 827 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

0.52

D;D;D

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.24

Sift

Benign

0.084

T;T

Sift4G

Uncertain

0.024

D;D

Polyphen

0.95

P;.

Vest4

0.72

MVP

0.87

MPC

0.44

ClinPred

0.35

GERP RS

5.4

Varity_R

0.40

gMVP

0.39

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