rs201106245

chr1-235809154-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4 BP6 BS1

The NM_000081.4(LYST):c.1664A>C(p.His555Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.48

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 Likely_benign. Variant got -3 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=0.39767122).
• BP6: Variant 1-235809154-T-G is Benign according to our data. Variant chr1-235809154-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572466.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000118 (18/152312) while in subpopulation AMR AF= 0.00111 (17/15290). AF 95% confidence interval is 0.000708. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.1664A>C	p.His555Pro	missense_variant	5/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.1664A>C	p.His555Pro	missense_variant	5/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000267 AC: 67 AN: 250822 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135536

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00153

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: 0.00

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461730 Hom.: 0 Cov.: 37 AF XY: 0.0000550 AC XY: 40 AN XY: 727178

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00157

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000305 Hom.: 0

Bravo AF: 0.000340

ExAC AF: 0.000198 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 09, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 555 of the LYST protein (p.His555Pro). This variant is present in population databases (rs201106245, gnomAD 0.2%). This missense change has been observed in individual(s) with systemic juvenile idiopathic arthritis without macrophage activation syndrome (PMID: 25047945). ClinVar contains an entry for this variant (Variation ID: 572466). 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.0034	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.60
Sift	Benign	0.055	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.87
MVP		0.81
MPC		0.55
ClinPred		0.19	T
GERP RS		5.6
Varity_R		0.76
gMVP		0.78

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: rs201106245; hg19: chr1-235972454;