1-235775088-TAA-TAAA

Variant names:

• chr1-235775088-T-TA
• rs557545474
• NM_000081.4:c.5461-3dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000081.4(LYST):​c.5461-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,114,534 control chromosomes in the GnomAD database, including 45 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 32)
  • Exomes 𝑓: 0.044 (26 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 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 -9 ACMG points.

• BP6: Variant 1-235775088-T-TA is Benign according to our data. Variant chr1-235775088-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211409.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0111 (1627/146228) while in subpopulation SAS AF = 0.0197 (92/4660). AF 95% confidence interval is 0.0165. There are 19 homozygotes in GnomAd4. There are 817 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1626 AN: 146176 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00284

Gnomad AMI AF: 0.00552

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.00678

Gnomad EAS AF: 0.000983

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00906

GnomAD2 exomes AF: 0.0521 AC: 5054 AN: 96916 AF XY: 0.0521

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.0125

Gnomad FIN exome AF: 0.0522

Gnomad NFE exome AF: 0.0426

Gnomad OTH exome AF: 0.0507

GnomAD4 exome AF: 0.0438 AC: 42404 AN: 968306 Hom.: 26 Cov.: 27 AF XY: 0.0428 AC XY: 20542 AN XY: 480436

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

African (AFR) AF: 0.0266 AC: 578 AN: 21702

American (AMR) AF: 0.0645 AC: 1878 AN: 29114

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 486 AN: 16072

East Asian (EAS) AF: 0.0139 AC: 333 AN: 23938

South Asian (SAS) AF: 0.0437 AC: 2466 AN: 56378

European-Finnish (FIN) AF: 0.0344 AC: 1150 AN: 33470

Middle Eastern (MID) AF: 0.0281 AC: 115 AN: 4088

European-Non Finnish (NFE) AF: 0.0454 AC: 33787 AN: 744488

Other (OTH) AF: 0.0412 AC: 1611 AN: 39056

⚠️ 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: 0.0111 AC: 1627 AN: 146228 Hom.: 19 Cov.: 32 AF XY: 0.0115 AC XY: 817 AN XY: 71144

African (AFR) AF: 0.00283 AC: 114 AN: 40228

American (AMR) AF: 0.0182 AC: 268 AN: 14688

Ashkenazi Jewish (ASJ) AF: 0.00678 AC: 23 AN: 3390

East Asian (EAS) AF: 0.000986 AC: 5 AN: 5072

South Asian (SAS) AF: 0.0197 AC: 92 AN: 4660

European-Finnish (FIN) AF: 0.0168 AC: 151 AN: 8988

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.0144 AC: 949 AN: 66008

Other (OTH) AF: 0.00897 AC: 18 AN: 2006

Alfa AF: 0.0349 Hom.: 0

Bravo AF: 0.0107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	Chédiak-Higashi syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=94/6	polymorphism

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: rs557545474; hg19: chr1-235938388; COSMIC: COSV67707507;