rs201382097

Variant names:

• chr1-235782091-C-A
• rs201382097
• NM_000081.4:c.4863-4G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-235782091-C-A
• chr1-235782091-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000081.4(LYST):​c.4863-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001281
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0160
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-235782091-C-A is Pathogenic according to our data. Variant chr1-235782091-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 561991.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.4863-4G>T		splice_region_variant, intron_variant	Intron 14 of 52	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.4863-4G>T		splice_region_variant, intron_variant	Intron 14 of 52	5	NM_000081.4	ENSP00000374443.2
LYST	ENST00000489585.5	n.4863-4G>T		splice_region_variant, intron_variant	Intron 14 of 22	1		ENSP00000513166.1
LYST	ENST00000697178.1	n.*287-4G>T		splice_region_variant, intron_variant	Intron 13 of 51			ENSP00000513163.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245346 AF XY: 0.00000752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456138 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724374

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.00 AC: 0 AN: 85946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108352

Other (OTH) AF: 0.00 AC: 0 AN: 60142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Chédiak-Higashi syndrome Pathogenic:1

Apr 23, 2018

Fan Lab, Zhengzhou University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This splicing mutation was identified in a 4-year-old female patient who diagnosed with Chediak-Higashi Syndrome. It was inherited from the patient's father and considered as a part of a compound heterozygote together with another heterozygous mutation c.5719A>G in CHS1/LYST gene. The patient showed typical clinical features of CHS, while her parents were healthy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.5
DANN	Benign	0.66
PhyloP100		-0.016

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.080		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: rs201382097; hg19: chr1-235945391;