NM_000081.4:c.5373G>A

Variant names:

• chr1-235777150-C-T
• rs2273584
• NM_000081.4:c.5373G>A

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.5373G>A​(p.Lys1791Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,612,208 control chromosomes in the GnomAD database, including 123,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13097 hom., cov: 31)
  • Exomes 𝑓: 0.38 (110677 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.621
• Publications: 14 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=-0.69).
• BP6: Variant 1-235777150-C-T is Benign according to our data. Variant chr1-235777150-C-T is described in ClinVar as Benign. ClinVar VariationId is 254927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.621 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.487 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	NM_000081.4	MANE Select	c.5373G>A	p.Lys1791Lys	synonymous	Exon 17 of 53	NP_000072.2
	LYST	NM_001301365.1		c.5373G>A	p.Lys1791Lys	synonymous	Exon 17 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.5373G>A	p.Lys1791Lys	synonymous	Exon 17 of 53	ENSP00000374443.2
	LYST	ENST00000489585.5	TSL:1	n.5373G>A		non_coding_transcript_exon	Exon 17 of 23	ENSP00000513166.1
	LYST	ENST00000461526.2	TSL:3	n.48G>A		non_coding_transcript_exon	Exon 1 of 28	ENSP00000513165.1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61329 AN: 151738 Hom.: 13083 Cov.: 31

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.0626

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.344 AC: 86280 AN: 251078 AF XY: 0.338

Gnomad AFR exome AF: 0.501

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.0588

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.381 AC: 556878 AN: 1460352 Hom.: 110677 Cov.: 33 AF XY: 0.376 AC XY: 273142 AN XY: 726616

African (AFR) AF: 0.499 AC: 16672 AN: 33428

American (AMR) AF: 0.284 AC: 12699 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9545 AN: 26112

East Asian (EAS) AF: 0.0856 AC: 3388 AN: 39598

South Asian (SAS) AF: 0.205 AC: 17661 AN: 86242

European-Finnish (FIN) AF: 0.434 AC: 23177 AN: 53404

Middle Eastern (MID) AF: 0.324 AC: 1864 AN: 5756

European-Non Finnish (NFE) AF: 0.405 AC: 449809 AN: 1110752

Other (OTH) AF: 0.366 AC: 22063 AN: 60340

GnomAD4 genome AF: 0.404 AC: 61392 AN: 151856 Hom.: 13097 Cov.: 31 AF XY: 0.397 AC XY: 29477 AN XY: 74204

African (AFR) AF: 0.493 AC: 20435 AN: 41444

American (AMR) AF: 0.326 AC: 4972 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1248 AN: 3472

East Asian (EAS) AF: 0.0628 AC: 325 AN: 5176

South Asian (SAS) AF: 0.189 AC: 908 AN: 4816

European-Finnish (FIN) AF: 0.433 AC: 4544 AN: 10496

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27674 AN: 67912

Other (OTH) AF: 0.389 AC: 817 AN: 2102

Alfa AF: 0.409 Hom.: 8350

Bravo AF: 0.401

Asia WGS AF: 0.153 AC: 532 AN: 3468

EpiCase AF: 0.391

EpiControl AF: 0.399

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Chédiak-Higashi syndrome (2)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.2
DANN	Benign	0.56
PhyloP100		0.62
Mutation Taster		=96/4	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: rs2273584; hg19: chr1-235940450; COSMIC: COSV67705051;