1-235766204-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000081.4(LYST):c.5996T>A(p.Val1999Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V1999V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.99

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LYST
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 1-235766204-A-T is Pathogenic according to our data. Variant chr1-235766204-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 3817.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.5996T>A	p.Val1999Asp	missense_variant	21/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.5996T>A	p.Val1999Asp	missense_variant	21/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Chediak-Higashi syndrome, adult type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 15, 2002

- -

Chédiak-Higashi syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.88		Gain of disorder (P = 0.0283);
MVP		0.87
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.88
gMVP		0.90

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: rs28942077; hg19: chr1-235929504;