rs750338502

chr1-235770249-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000081.4(LYST):c.5833G>A(p.Ala1945Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1945A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.08

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LYST
• BP4: Computational evidence support a benign effect (MetaRNN=0.17607522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.5833G>A	p.Ala1945Thr	missense_variant	20/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.5833G>A	p.Ala1945Thr	missense_variant	20/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250982 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461522 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1945 of the LYST protein (p.Ala1945Thr). This variant is present in population databases (rs750338502, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 525164). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LYST protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

The c.5833G>A (p.A1945T) alteration is located in exon 20 (coding exon 18) of the LYST gene. This alteration results from a G to A substitution at nucleotide position 5833, causing the alanine (A) at amino acid position 1945 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.086	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.072
Sift	Benign	0.26	T
Sift4G	Benign	0.26	T
Polyphen		0.27	B
Vest4		0.30
MutPred		0.31		Loss of stability (P = 0.0269);
MVP		0.48
ClinPred		0.46	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.11

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: rs750338502; hg19: chr1-235933549;