rs11583387

Variant names:

• chr1-235791850-G-A
• rs11583387
• NM_000081.4:c.4392C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000081.4(LYST):​c.4392C>T​(p.Asn1464Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,614,028 control chromosomes in the GnomAD database, including 9,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (710 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8917 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.08
• Publications: 13 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-235791850-G-A is Benign according to our data. Variant chr1-235791850-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

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.4392C>T	p.Asn1464Asn	synonymous	Exon 12 of 53	NP_000072.2
	LYST	NM_001301365.1		c.4392C>T	p.Asn1464Asn	synonymous	Exon 12 of 53	NP_001288294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.4392C>T	p.Asn1464Asn	synonymous	Exon 12 of 53	ENSP00000374443.2
	LYST	ENST00000465349.5	TSL:1	n.4943C>T		non_coding_transcript_exon	Exon 12 of 12
	LYST	ENST00000489585.5	TSL:1	n.4392C>T		non_coding_transcript_exon	Exon 12 of 23	ENSP00000513166.1

Frequencies

GnomAD3 genomes AF: 0.0908 AC: 13809 AN: 152134 Hom.: 711 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0921

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0882 AC: 22154 AN: 251212 AF XY: 0.0876

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.0778

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0491

Gnomad FIN exome AF: 0.0827

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.107 AC: 156298 AN: 1461776 Hom.: 8917 Cov.: 32 AF XY: 0.105 AC XY: 76584 AN XY: 727202

African (AFR) AF: 0.0641 AC: 2147 AN: 33480

American (AMR) AF: 0.0800 AC: 3577 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2860 AN: 26136

East Asian (EAS) AF: 0.0493 AC: 1956 AN: 39694

South Asian (SAS) AF: 0.0388 AC: 3344 AN: 86256

European-Finnish (FIN) AF: 0.0860 AC: 4594 AN: 53420

Middle Eastern (MID) AF: 0.136 AC: 784 AN: 5768

European-Non Finnish (NFE) AF: 0.118 AC: 130769 AN: 1111906

Other (OTH) AF: 0.104 AC: 6267 AN: 60392

GnomAD4 genome AF: 0.0907 AC: 13807 AN: 152252 Hom.: 710 Cov.: 32 AF XY: 0.0882 AC XY: 6570 AN XY: 74450

African (AFR) AF: 0.0641 AC: 2663 AN: 41538

American (AMR) AF: 0.0919 AC: 1406 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3470

East Asian (EAS) AF: 0.0434 AC: 225 AN: 5190

South Asian (SAS) AF: 0.0306 AC: 148 AN: 4830

European-Finnish (FIN) AF: 0.0873 AC: 926 AN: 10602

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7672 AN: 67996

Other (OTH) AF: 0.105 AC: 223 AN: 2114

Alfa AF: 0.104 Hom.: 567

Bravo AF: 0.0921

Asia WGS AF: 0.0390 AC: 136 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.121

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.7
DANN	Benign	0.67
PhyloP100		3.1
Mutation Taster		=98/2	polymorphism (auto)

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: rs11583387; hg19: chr1-235955150; COSMIC: COSV108238992; COSMIC: COSV108238992;