rs33998267

chr1-235830409-G-Achr1-235830409-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000081.4(LYST):c.9C>T(p.Thr3=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,611,378 control chromosomes in the GnomAD database, including 220 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 0.011 (8 hom., cov: 32)
  • Exomes 𝑓: 0.016 (212 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.148

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-235830409-G-A is Benign according to our data. Variant chr1-235830409-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254942.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}. Variant chr1-235830409-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.148 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0115 (1745/151914) while in subpopulation AMR AF= 0.0184 (280/15250). AF 95% confidence interval is 0.0166. There are 8 homozygotes in gnomad4. There are 794 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.9C>T	p.Thr3=	synonymous_variant	3/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.9C>T	p.Thr3=	synonymous_variant	3/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1746 AN: 151796 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.00723

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0226

GnomAD3 exomes AF: 0.0115 AC: 2859 AN: 249432 Hom.: 25 AF XY: 0.0116 AC XY: 1563 AN XY: 134846

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00211

Gnomad FIN exome AF: 0.00704

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0158 AC: 23033 AN: 1459464 Hom.: 212 Cov.: 30 AF XY: 0.0154 AC XY: 11159 AN XY: 726150

Gnomad4 AFR exome AF: 0.00240

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00295

Gnomad4 FIN exome AF: 0.00806

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0115 AC: 1745 AN: 151914 Hom.: 8 Cov.: 32 AF XY: 0.0107 AC XY: 794 AN XY: 74234

Gnomad4 AFR AF: 0.00282

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00313

Gnomad4 FIN AF: 0.00723

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0224

Alfa AF: 0.0151 Hom.: 5

Bravo AF: 0.0127

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0163

EpiControl AF: 0.0170

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	1.5
Dann	Benign	0.85

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: rs33998267; hg19: chr1-235993709;