chr1-235759371-T-G

Position:

chr1-235759371-T-G

Variant summary

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

The NM_000081.4(LYST):c.6482A>C(p.Glu2161Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00511 in 1,614,230 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.0042 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 42 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 5.56

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=0.0030755103).

BP6

Variant 1-235759371-T-G is Benign according to our data. Variant chr1-235759371-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254931.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=3}. Variant chr1-235759371-T-G is described in Lovd as [Benign]. Variant chr1-235759371-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00421 (641/152380) while in subpopulation AMR AF= 0.00588 (90/15306). AF 95% confidence interval is 0.0049. There are 5 homozygotes in gnomad4. There are 286 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4 linkuse as main transcript	c.6482A>C	p.Glu2161Ala	missense_variant	23/53	ENST00000389793.7	NP_000072.2	Q99698-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7 linkuse as main transcript	c.6482A>C	p.Glu2161Ala	missense_variant	23/53	5	NM_000081.4	ENSP00000374443.2		Q99698-1

Frequencies

GnomAD3 genomes

AF:

0.00422

AC:

642

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.0354

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00525

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00476

AC:

1197

AN:

251264

Hom.:

AF XY:

0.00496

AC XY:

673

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.0328

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00278

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00517

Gnomad OTH exome

AF:

0.00767

GnomAD4 exome

AF:

0.00520

AC:

7603

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00527

AC XY:

3834

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00400

Gnomad4 ASJ exome

AF:

0.0354

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00289

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00516

Gnomad4 OTH exome

AF:

0.00692

GnomAD4 genome

AF:

0.00421

AC:

641

AN:

152380

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

286

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00588

Gnomad4 ASJ

AF:

0.0354

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00525

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00618

Hom.:

Bravo

AF:

0.00468

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00428

AC:

519

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00600

EpiControl

AF:

0.00640

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chédiak-Higashi syndrome

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Apr 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 23, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 3.3% [338/10366]; including in 7 homozygotes; https://gnomad.broadinstitute.org/variant/1-235922671-T-G?dataset=gnomad_r2_1), and in ClinVar, with several laboratories classifying it as benign or likely benign (Variation ID: 254931). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LYST: BP4, BS2 -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.5

REVEL

Benign

0.18

Sift

Uncertain

0.028

Sift4G

Uncertain

0.014

Polyphen

0.23

Vest4

0.21

MVP

0.60

ClinPred

0.036

GERP RS

2.8

Varity_R

0.099

gMVP

0.38

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