1-235775088-TAA-TAAAA

Variant names:

• chr1-235775088-T-TAA
• rs557545474
• NM_000081.4:c.5461-4_5461-3dupTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000081.4(LYST):​c.5461-4_5461-3dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,262,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.462
• Publications: 2 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 -12 ACMG points.

• BP6: Variant 1-235775088-T-TAA is Benign according to our data. Variant chr1-235775088-T-TAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1167294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000396 (58/146282) while in subpopulation EAS AF = 0.00355 (18/5072). AF 95% confidence interval is 0.00229. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.5461-4_5461-3dupTT		splice_region intron	N/A	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.5461-4_5461-3dupTT		splice_region intron	N/A	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.5461-3_5461-2insTT		splice_region intron	N/A	ENSP00000374443.2	Q99698-1
	LYST	ENST00000489585.5	TSL:1	n.5461-3_5461-2insTT		splice_region intron	N/A	ENSP00000513166.1	Q99698-2
	LYST	ENST00000461526.2	TSL:3	n.136-3_136-2insTT		splice_region intron	N/A	ENSP00000513165.1	A0A8V8TL52

Frequencies

GnomAD3 genomes AF: 0.000397 AC: 58 AN: 146230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00354

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00112 AC: 109 AN: 96916 AF XY: 0.00102

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0125

Gnomad FIN exome AF: 0.000119

Gnomad NFE exome AF: 0.0000639

Gnomad OTH exome AF: 0.000448

GnomAD4 exome AF: 0.000296 AC: 330 AN: 1116394 Hom.: 0 Cov.: 27 AF XY: 0.000270 AC XY: 150 AN XY: 556488

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00130 AC: 33 AN: 25386

American (AMR) AF: 0.0000884 AC: 3 AN: 33952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19260

East Asian (EAS) AF: 0.00635 AC: 186 AN: 29284

South Asian (SAS) AF: 0.000135 AC: 9 AN: 66714

European-Finnish (FIN) AF: 0.0000261 AC: 1 AN: 38296

Middle Eastern (MID) AF: 0.000220 AC: 1 AN: 4552

European-Non Finnish (NFE) AF: 0.000102 AC: 87 AN: 853316

Other (OTH) AF: 0.000219 AC: 10 AN: 45634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000396 AC: 58 AN: 146282 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 22 AN XY: 71174

African (AFR) AF: 0.000870 AC: 35 AN: 40230

American (AMR) AF: 0.000272 AC: 4 AN: 14692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00355 AC: 18 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66026

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000559

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs557545474; hg19: chr1-235938388;