rs34702903

Positions:

chr1-235731066-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000081.4(LYST):c.8913T>G(p.Asn2971Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,613,680 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0042 ( 15 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 2.21

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 -12 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=0.02045229).

BP6

Variant 1-235731066-A-C is Benign according to our data. Variant chr1-235731066-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525179.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}. Variant chr1-235731066-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (394/152290) while in subpopulation NFE AF= 0.00447 (304/68008). AF 95% confidence interval is 0.00406. There are 1 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4 linkuse as main transcript	c.8913T>G	p.Asn2971Lys	missense_variant	35/53	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.8913T>G	p.Asn2971Lys	missense_variant	35/53	5	NM_000081.4	ENSP00000374443	P1	Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.00259

AC:

394

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00447

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00244

AC:

614

AN:

251384

Hom.:

AF XY:

0.00246

AC XY:

334

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00444

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00422

AC:

6166

AN:

1461390

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

2994

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.00521

Gnomad4 OTH exome

AF:

0.00287

GnomAD4 genome

AF:

0.00259

AC:

394

AN:

152290

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

169

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00447

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00415

Hom.:

Bravo

AF:

0.00275

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00216

AC:

262

EpiCase

AF:

0.00485

EpiControl

AF:

0.00468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 14, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2019	Identified as a single heterozygous variant in two individuals with fatal H1N1 influenza and identified with another LYST variant in another individual with cerebellar ataxia, but limited phenotypic information was provided on these individuals (Schulert et al., 2016; Coutelier et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29482223, 26597256) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -

Chédiak-Higashi syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 30, 2022	LYST NM_000081.3 exon 35 p.Asn2971Lys (c.8913T>G): This variant has been reported in the literature in at least 1 individual with cerebellar ataxia (Coutelier 2018 PMID:29482223). This variant is present in 0.4% (580/129120) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235894366-A-C). This variant is present in ClinVar (Variation ID:525179). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2023	Variant summary: LYST c.8913T>G (p.Asn2971Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 251384 control chromosomes. The observed variant frequency is approximately 2.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome phenotype (0.0011), suggesting that the variant is benign. c.8913T>G has been reported in the literature in settings of whole exome or multigene panel testing in individuals affected with clinical features that have been reported in Chediak-Higashi Syndrome, including cerebellar ataxia, reported as a VUS with compound heterozygous genotype (e.g.Coutelier_2018), fatal H1N1, reported as a VUS in a heterozygous genotype (e.g. Schulert_2016), unspecified inherited bleeding disorder with unspecified genotype (e.g. Leinoe_2017), and unclassified neuroinflammatory disease with isolated incidence of hemiplegia and ataxia as a compound heterozygous genotype with variants in multiple neuroinflammatory genes (e.g.McCreary_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Chediak-Higashi Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29482223, 28748566, 31664448, 26597256). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 08, 2021	- -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2019

- -

LYST-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

0.022

Eigen_PC

Benign

0.064

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.039

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.99

REVEL

Benign

0.096

Sift

Benign

0.66

Sift4G

Uncertain

0.054

Polyphen

0.90

Vest4

0.74

MutPred

0.41

Gain of methylation at N2971 (P = 0.0065);

MVP

0.66

ClinPred

0.030

GERP RS

2.1

Varity_R

0.16

gMVP

0.67

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