rs144597913

Positions:

• chr1-235734531-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000081.4(LYST):​c.8487C>T​(p.Ile2829=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,634 control chromosomes in the GnomAD database, including 3 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 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.13

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-235734531-G-A is Benign according to our data. Variant chr1-235734531-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522322.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=1}. Variant chr1-235734531-G-A is described in Lovd as [Benign]. Variant chr1-235734531-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00124 (189/152210) while in subpopulation NFE AF= 0.00241 (164/67962). AF 95% confidence interval is 0.00211. There are 0 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.8487C>T	p.Ile2829=	synonymous_variant	32/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.8487C>T	p.Ile2829=	synonymous_variant	32/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00138 AC: 347 AN: 251298 Hom.: 1 AF XY: 0.00141 AC XY: 192 AN XY: 135802

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00170 AC: 2482 AN: 1461424 Hom.: 3 Cov.: 30 AF XY: 0.00169 AC XY: 1231 AN XY: 727030

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000928

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74424

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00241

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00114

EpiCase AF: 0.00224

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

LYST: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	4.7
DANN	Benign	0.72

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: rs144597913; hg19: chr1-235897831;