rs777389303

chr1-235812973-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_000081.4(LYST):c.281C>T(p.Thr94Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,598,090 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T94A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: LYST NM_000081.4 missense, splice_region
• Scores: Splicing: ADA: 0.01489
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 3.01

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LYST
• BP4: Computational evidence support a benign effect (MetaRNN=0.007193178).
• BP6: Variant 1-235812973-G-A is Benign according to our data. Variant chr1-235812973-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211408.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000105 (16/152264) while in subpopulation EAS AF= 0.00309 (16/5184). AF 95% confidence interval is 0.00194. There are 0 homozygotes in gnomad4. There are 9 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.281C>T	p.Thr94Ile	missense_variant, splice_region_variant	4/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.281C>T	p.Thr94Ile	missense_variant, splice_region_variant	4/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000240 AC: 60 AN: 250382 Hom.: 1 AF XY: 0.000237 AC XY: 32 AN XY: 135292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00317

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000144 AC: 208 AN: 1445826 Hom.: 2 Cov.: 28 AF XY: 0.000137 AC XY: 99 AN XY: 720258

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00428

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.000601

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:2 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	LYST NM_000081.3 exon 4 p.Thr94Ile (c.281C>T):This variant has been reported in the literature in at least 1 individual with T-cell deficiency as a compound heterozygote (StrayPedersen 2016 PMID:27577878, Yu 2016 PMID:2748032). Of note, the variant that was found in trans in this individual (p.Arg2261His) has been reported in ClinVar as Benign by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/254933/). This variant is present in 0.3% (67/19846) of East Asian alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235976273-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:211408). This variant amino acid Isoleucine (Ile) is present in >15 species including mammals, 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 is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2023	Variant summary: LYST c.281C>T (p.Thr94Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 327814 control chromosomes, predominantly at a frequency of 0.0053 within the Japanese subpopulation, including 2 homozygotes (gnomAD and jMorp databases; Tadaka_2021). The observed variant frequency within Japanese control individuals in the jMorp database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian/Japanese origin. c.281C>T has been reported in the literature in at least one individual affected with T-cell deficiency, CD4 lymphopenia, and interstitial lung disease (e.g., Yu_2016, Stray-Pedersen_2017), however without strong evidence for causality (e.g., absence of a second pathogenic LYST variant). These reports therefore 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: 27577878, 27484032, 33179747). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n = 3; likely benign, n = 2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 04, 2015	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2019

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	13
Dann	Benign	0.65
DEOGEN2	Benign	0.097	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.13
Sift	Benign	0.21	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0	B;.
Vest4		0.19
MutPred		0.26		Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);
MVP		0.25
MPC		0.083
ClinPred		0.042	T
GERP RS		2.2
Varity_R		0.033
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.13		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: rs777389303; hg19: chr1-235976273; COSMIC: COSV67705741;