rs201821563

Variant names:

• chr1-235753119-G-T
• rs201821563
• NM_000081.4:c.7385C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000081.4(LYST):​c.7385C>A​(p.Ala2462Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,608,906 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.38
• Publications: 4 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.7385C>A	p.Ala2462Glu	missense	Exon 26 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.7385C>A	p.Ala2462Glu	missense	Exon 26 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.7385C>A	p.Ala2462Glu	missense	Exon 26 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697241.1		c.1865C>A	p.Ala622Glu	missense	Exon 10 of 26	ENSP00000513206.1	A0A8V8TM69
	LYST	ENST00000461526.2	TSL:3	n.2060C>A		non_coding_transcript_exon	Exon 10 of 28	ENSP00000513165.1	A0A8V8TL52

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000371 AC: 93 AN: 250924 AF XY: 0.000317

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.000520

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000195 AC: 284 AN: 1456854 Hom.: 1 Cov.: 28 AF XY: 0.000189 AC XY: 137 AN XY: 725094

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26058

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 86146

European-Finnish (FIN) AF: 0.000955 AC: 51 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.000170 AC: 188 AN: 1107710

Other (OTH) AF: 0.000565 AC: 34 AN: 60228

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41494

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000568 AC: 69

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Chédiak-Higashi syndrome (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.015	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.77
MVP		0.63
ClinPred		0.42	T
GERP RS		5.3
Varity_R		0.65
gMVP		0.73
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs201821563; hg19: chr1-235916419;