1-235766204-A-T

Variant names:

• chr1-235766204-A-T
• rs28942077
• NM_000081.4:c.5996T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 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
• Publications: 8 publications found

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]

LYST Gene-Disease associations (from GenCC):

• Chediak-Higashi syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• attenuated Chédiak-Higashi syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 3817.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	NM_000081.4	MANE Select	c.5996T>A	p.Val1999Asp	missense	Exon 21 of 53	NP_000072.2
	LYST	NM_001301365.1		c.5996T>A	p.Val1999Asp	missense	Exon 21 of 53	NP_001288294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.5996T>A	p.Val1999Asp	missense	Exon 21 of 53	ENSP00000374443.2
	LYST	ENST00000489585.5	TSL:1	n.5961+35T>A		intron	N/A	ENSP00000513166.1
	LYST	ENST00000697241.1		c.428T>A	p.Val143Asp	missense	Exon 4 of 26	ENSP00000513206.1

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

Feb 15, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Chédiak-Higashi syndrome Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.0
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
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28942077; hg19: chr1-235929504;