rs771833094

Positions:

• chr1-235809707-G-A
• chr1-235809707-G-C

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.1111C>T​(p.Pro371Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.905

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 in gene, where missense usually causes diseases (based on misZ statistic), LYST. . Trascript score misZ 4.0845 (greater than threshold 3.09). GenCC has associacion of gene with Chediak-Higashi syndrome, attenuated Chédiak-Higashi syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10133606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4	c.1111C>T	p.Pro371Ser	missense_variant	5/53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.1111C>T	p.Pro371Ser	missense_variant	5/53	5	NM_000081.4	ENSP00000374443	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250674 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461352 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 16, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with LYST-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 371 of the LYST protein (p.Pro371Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. 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	Benign	0.089
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.096	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.022
Sift	Benign	0.12	T;T
Sift4G	Benign	0.080	T;T
Polyphen		0.013	B;.
Vest4		0.14
MutPred		0.28		Gain of phosphorylation at P371 (P = 0.0444);Gain of phosphorylation at P371 (P = 0.0444);
MVP		0.29
MPC		0.38
ClinPred		0.16	T
GERP RS		3.6
Varity_R		0.071
gMVP		0.10

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: rs771833094; hg19: chr1-235973007;