1-235693382-C-T

Variant names:

• chr1-235693382-C-T
• rs148389013
• NM_000081.4:c.10669G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000081.4(LYST):​c.10669G>A​(p.Val3557Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3557L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.650
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp
• attenuated Chédiak-Higashi syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296841 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03667158).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	NM_000081.4	MANE Select	c.10669G>A	p.Val3557Ile	missense	Exon 47 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.10669G>A	p.Val3557Ile	missense	Exon 47 of 53	NP_001288294.1	Q99698-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.10669G>A	p.Val3557Ile	missense	Exon 47 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697235.1		c.1219G>A	p.Val407Ile	missense	Exon 9 of 15	ENSP00000513202.1	A0A8V8TL78
	LYST	ENST00000462376.2	TSL:4	n.2079G>A		non_coding_transcript_exon	Exon 5 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Chédiak-Higashi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.9
DANN	Benign	0.49
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.60	N
PhyloP100		0.65
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.022
Sift	Benign	0.83	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.080
MutPred		0.22		Gain of glycosylation at P3555 (P = 0.2025)
MVP		0.30
ClinPred		0.050	T
GERP RS		-4.1
Varity_R		0.034
gMVP		0.026
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs148389013; hg19: chr1-235856682;