rs141317482

Positions:

• chr1-235830422-G-A
• chr1-235830422-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000081.4(LYST):​c.-5C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00602 in 1,603,548 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (23 hom.)
• Consequence: LYST NM_000081.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.63

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 1-235830422-G-A is Benign according to our data. Variant chr1-235830422-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254905.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00375 (570/151834) while in subpopulation NFE AF= 0.00599 (407/67970). AF 95% confidence interval is 0.00551. There are 2 homozygotes in gnomad4. There are 253 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4	c.-5C>T		5_prime_UTR_premature_start_codon_gain_variant	3/53	ENST00000389793.7	NP_000072.2
LYST	NM_000081.4	c.-5C>T		splice_region_variant	3/53	ENST00000389793.7	NP_000072.2
LYST	NM_000081.4	c.-5C>T		5_prime_UTR_variant	3/53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.-5C>T		5_prime_UTR_premature_start_codon_gain_variant	3/53	5	NM_000081.4	ENSP00000374443.2
LYST	ENST00000389793.7	c.-5C>T		splice_region_variant	3/53	5	NM_000081.4	ENSP00000374443.2
LYST	ENST00000389793.7	c.-5C>T		5_prime_UTR_variant	3/53	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 570 AN: 151720 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00599

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00373 AC: 907 AN: 243356 Hom.: 1 AF XY: 0.00372 AC XY: 490 AN XY: 131762

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00155

Gnomad FIN exome AF: 0.00605

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00626 AC: 9089 AN: 1451714 Hom.: 23 Cov.: 29 AF XY: 0.00610 AC XY: 4405 AN XY: 722394

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.000578

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.00634

Gnomad4 NFE exome AF: 0.00737

Gnomad4 OTH exome AF: 0.00556

GnomAD4 genome AF: 0.00375 AC: 570 AN: 151834 Hom.: 2 Cov.: 32 AF XY: 0.00341 AC XY: 253 AN XY: 74170

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00243

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00599

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00407 Hom.: 3

Bravo AF: 0.00362

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

LYST: BP4, BS2 -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.88

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: rs141317482; hg19: chr1-235993722;