rs3768067

chr1-235810450-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_000081.4(LYST):c.368A>G(p.His123Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,609,896 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H123Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.619

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LYST
• BP4: Computational evidence support a benign effect (MetaRNN=0.006024182).
• BP6: Variant 1-235810450-T-C is Benign according to our data. Variant chr1-235810450-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 296434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-235810450-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000348 (53/152352) while in subpopulation EAS AF= 0.00867 (45/5188). AF 95% confidence interval is 0.00666. There are 1 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.368A>G	p.His123Arg	missense_variant	5/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.368A>G	p.His123Arg	missense_variant	5/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152234 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00865

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000877 AC: 216 AN: 246214 Hom.: 1 AF XY: 0.000774 AC XY: 103 AN XY: 133044

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0116

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000839

GnomAD4 exome AF: 0.000292 AC: 425 AN: 1457544 Hom.: 2 Cov.: 34 AF XY: 0.000295 AC XY: 214 AN XY: 725080

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00927

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000748

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152352 Hom.: 1 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00867

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000834 Hom.: 0

Bravo AF: 0.000563

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chédiak-Higashi syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 16, 2022	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 12, 2017

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	12
Dann	Benign	0.90
DEOGEN2	Benign	0.094	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.059
Sift	Benign	0.35	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.017	B;.
Vest4		0.065
MVP		0.38
MPC		0.10
ClinPred		0.017	T
GERP RS		2.1
Varity_R		0.085
gMVP		0.13

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: rs3768067; hg19: chr1-235973750; COSMIC: COSV67704683;