rs115330112

chr1-235775029-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000081.4(LYST):c.5518T>G(p.Ser1840Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00721 in 1,611,734 control chromosomes in the GnomAD database, including 60 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1840L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (58 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 3.94

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LYST
• BP4: Computational evidence support a benign effect (MetaRNN=0.009067118).
• BP6: Variant 1-235775029-A-C is Benign according to our data. Variant chr1-235775029-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235239.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=8}. Variant chr1-235775029-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00477 (726/152290) while in subpopulation NFE AF= 0.00792 (539/68030). AF 95% confidence interval is 0.00737. There are 2 homozygotes in gnomad4. There are 315 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.5518T>G	p.Ser1840Ala	missense_variant	18/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.5518T>G	p.Ser1840Ala	missense_variant	18/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 726 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00792

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00439 AC: 1099 AN: 250356 Hom.: 5 AF XY: 0.00435 AC XY: 589 AN XY: 135376

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.000940

Gnomad NFE exome AF: 0.00749

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00747 AC: 10900 AN: 1459444 Hom.: 58 Cov.: 30 AF XY: 0.00725 AC XY: 5265 AN XY: 726190

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00899

Gnomad4 OTH exome AF: 0.00635

GnomAD4 genome AF: 0.00477 AC: 726 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74458

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00792

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00695 Hom.: 9

Bravo AF: 0.00454

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00460 AC: 559

Asia WGS AF: 0.000289 AC: 1 AN: 3472

EpiCase AF: 0.00704

EpiControl AF: 0.00705

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Benign:6

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 0.7% (539/68038) including 2 homozygotes (https://gnomad.broadinstitute.org/variant/1-235775029-A-C?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign or Likely benign (Variation ID:235239). This variant amino acid Alanine (Ala) is present in multiple species including at least one mammal and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Benign:4

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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	LYST: BS2 -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2016	- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.089
Sift	Benign	0.35	T
Sift4G	Uncertain	0.017	D
Polyphen		0.0010	B
Vest4		0.43
MVP		0.62
ClinPred		0.014	T
GERP RS		4.1
Varity_R		0.13
gMVP		0.19

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

Other links and lift over

dbSNP: rs115330112; hg19: chr1-235938329;