1-235775088-TAA-TA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_000081.4(LYST):​c.5461-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 1,036,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.031 (0 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0378) population. However there is too low homozygotes in high coverage region: (expected more than 188, got 0).
• BP6: Variant 1-235775088-TA-T is Benign according to our data. Variant chr1-235775088-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 703786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Frequencies

GnomAD3 genomes AF: 0.000308 AC: 45 AN: 145928 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000614

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000212

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0551 AC: 5336 AN: 96916 AF XY: 0.0575

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.0626

Gnomad ASJ exome AF: 0.0591

Gnomad EAS exome AF: 0.0470

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0314 AC: 27947 AN: 890892 Hom.: 0 Cov.: 27 AF XY: 0.0308 AC XY: 13552 AN XY: 439346

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

African (AFR) AF: 0.0326 AC: 643 AN: 19744

American (AMR) AF: 0.0399 AC: 982 AN: 24628

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 450 AN: 13470

East Asian (EAS) AF: 0.0235 AC: 491 AN: 20930

South Asian (SAS) AF: 0.0350 AC: 1661 AN: 47412

European-Finnish (FIN) AF: 0.0321 AC: 951 AN: 29648

Middle Eastern (MID) AF: 0.0218 AC: 82 AN: 3758

European-Non Finnish (NFE) AF: 0.0310 AC: 21600 AN: 695682

Other (OTH) AF: 0.0305 AC: 1087 AN: 35620

⚠️ 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: 0.000308 AC: 45 AN: 145980 Hom.: 0 Cov.: 32 AF XY: 0.000338 AC XY: 24 AN XY: 70992

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

African (AFR) AF: 0.000299 AC: 12 AN: 40190

American (AMR) AF: 0.000614 AC: 9 AN: 14662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

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

European-Finnish (FIN) AF: 0.00112 AC: 10 AN: 8912

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

European-Non Finnish (NFE) AF: 0.000212 AC: 14 AN: 65904

Other (OTH) AF: 0.00 AC: 0 AN: 2004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0694 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: COSV67703018;