chr1-235808451-A-G

Variant names:

• chr1-235808451-A-G
• rs201398337
• NM_000081.4:c.2363+4T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000081.4(LYST):​c.2363+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,612,428 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Scores: Splicing: ADA: 0.01682
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.595
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Chediak-Higashi syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• attenuated Chédiak-Higashi syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 1-235808451-A-G is Benign according to our data. Variant chr1-235808451-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211407.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00132 (200/151572) while in subpopulation NFE AF = 0.00212 (144/67910). AF 95% confidence interval is 0.00184. There are 2 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.2363+4T>C		splice_region_variant, intron_variant	Intron 5 of 52	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.2363+4T>C		splice_region_variant, intron_variant	Intron 5 of 52	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 200 AN: 151572 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00210

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00133 AC: 333 AN: 250624 AF XY: 0.00131

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00469

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.00120 AC: 1760 AN: 1460856 Hom.: 4 Cov.: 34 AF XY: 0.00123 AC XY: 894 AN XY: 726654

African (AFR) AF: 0.0000898 AC: 3 AN: 33420

American (AMR) AF: 0.000381 AC: 17 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 98 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86186

European-Finnish (FIN) AF: 0.00275 AC: 147 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00127 AC: 1417 AN: 1111424

Other (OTH) AF: 0.00128 AC: 77 AN: 60346

GnomAD4 genome AF: 0.00132 AC: 200 AN: 151572 Hom.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 102 AN XY: 73958

African (AFR) AF: 0.000170 AC: 7 AN: 41228

American (AMR) AF: 0.000395 AC: 6 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00210 AC: 22 AN: 10498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 67910

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.00186 Hom.: 1

Bravo AF: 0.000937

EpiCase AF: 0.00180

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Aug 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LYST c.2363+4T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 computational tools predict no significant impact on normal splicing, and 1/4 predict the variant strengthens a cryptic 5' splice donor site 4nt into intron 5. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 281942 control chromosomes (gnomAD), predominantly at a frequency of 0.0021 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2363+4T>C in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign. -

Jun 16, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chédiak-Higashi syndrome Uncertain:1 Benign:1

Dec 08, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LYST NM_000081.3 exon 5 c.2363+4T>C: This variant has not been reported in the literature but is present in 0.2% (270/128716) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235971751-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:211407). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 07, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LYST: BP4, BS2 -

Autoinflammatory syndrome Benign:1

Sep 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		0.59
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.017
dbscSNV1_RF	Benign	0.11
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

Other links and lift over

dbSNP: rs201398337; hg19: chr1-235971751;