NM_000081.4:c.4956A>G

Variant names:

• chr1-235781994-T-C
• rs6696123
• NM_000081.4:c.4956A>G

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.4956A>G​(p.Leu1652Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,611,766 control chromosomes in the GnomAD database, including 124,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13168 hom., cov: 31)
  • Exomes 𝑓: 0.38 (111053 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.385
• Publications: 19 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-235781994-T-C is Benign according to our data. Variant chr1-235781994-T-C is described in ClinVar as Benign. ClinVar VariationId is 254923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.385 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 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.4956A>G	p.Leu1652Leu	synonymous	Exon 15 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.4956A>G	p.Leu1652Leu	synonymous	Exon 15 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.4956A>G	p.Leu1652Leu	synonymous	Exon 15 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000489585.5	TSL:1	n.4956A>G		non_coding_transcript_exon	Exon 15 of 23	ENSP00000513166.1	Q99698-2
	LYST	ENST00000697178.1		n.*380A>G		non_coding_transcript_exon	Exon 14 of 52	ENSP00000513163.1	A0A8V8TKT6

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61498 AN: 151856 Hom.: 13154 Cov.: 31

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.392

GnomAD2 exomes AF: 0.345 AC: 86470 AN: 250828 AF XY: 0.339

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.0588

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.382 AC: 557670 AN: 1459794 Hom.: 111053 Cov.: 34 AF XY: 0.377 AC XY: 273600 AN XY: 726288

African (AFR) AF: 0.500 AC: 16705 AN: 33432

American (AMR) AF: 0.284 AC: 12699 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9606 AN: 26130

East Asian (EAS) AF: 0.0856 AC: 3395 AN: 39640

South Asian (SAS) AF: 0.210 AC: 18106 AN: 86218

European-Finnish (FIN) AF: 0.434 AC: 23181 AN: 53370

Middle Eastern (MID) AF: 0.325 AC: 1869 AN: 5758

European-Non Finnish (NFE) AF: 0.405 AC: 450023 AN: 1110214

Other (OTH) AF: 0.366 AC: 22086 AN: 60314

GnomAD4 genome AF: 0.405 AC: 61559 AN: 151972 Hom.: 13168 Cov.: 31 AF XY: 0.398 AC XY: 29552 AN XY: 74266

African (AFR) AF: 0.495 AC: 20491 AN: 41436

American (AMR) AF: 0.326 AC: 4978 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1254 AN: 3468

East Asian (EAS) AF: 0.0632 AC: 327 AN: 5172

South Asian (SAS) AF: 0.195 AC: 942 AN: 4828

European-Finnish (FIN) AF: 0.433 AC: 4558 AN: 10520

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

European-Non Finnish (NFE) AF: 0.408 AC: 27720 AN: 67964

Other (OTH) AF: 0.389 AC: 821 AN: 2110

Alfa AF: 0.402 Hom.: 42720

Bravo AF: 0.401

Asia WGS AF: 0.156 AC: 544 AN: 3478

EpiCase AF: 0.391

EpiControl AF: 0.399

ClinVar

ClinVar submissions

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	-0.81
CADD	Benign	2.6
DANN	Benign	0.67
PhyloP100		-0.39
Mutation Taster		=100/0	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: rs6696123; hg19: chr1-235945294; COSMIC: COSV67705068;