1-235663082-TAAAA-TAAAAA

Variant names:

• chr1-235663082-T-TA
• rs36014994
• NM_000081.4:c.11268-5dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_000081.4(LYST):​c.11268-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.00026 (0 hom., cov: 0)
  • Exomes 𝑓: 0.017 (0 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.694
• Publications: 6 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 -5 ACMG points.

• BP6: Variant 1-235663082-T-TA is Benign according to our data. Variant chr1-235663082-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296343.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000261 (39/149444) while in subpopulation EAS AF = 0.00237 (12/5056). AF 95% confidence interval is 0.00137. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 0. 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.11268-5dupT		splice_region intron	N/A	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.11268-5dupT		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.11268-5_11268-4insT		splice_region intron	N/A	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697235.1		c.1818-5_1818-4insT		splice_region intron	N/A	ENSP00000513202.1	A0A8V8TL78
	LYST	ENST00000462376.2	TSL:4	n.3087-5_3087-4insT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000261 AC: 39 AN: 149358 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000471

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00237

Gnomad SAS AF: 0.000851

Gnomad FIN AF: 0.000404

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00771 AC: 1258 AN: 163066 AF XY: 0.00766

Gnomad AFR exome AF: 0.000427

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.00415

Gnomad EAS exome AF: 0.0305

Gnomad FIN exome AF: 0.00753

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00696

GnomAD4 exome AF: 0.0168 AC: 19516 AN: 1163230 Hom.: 0 Cov.: 0 AF XY: 0.0162 AC XY: 9447 AN XY: 582630

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

African (AFR) AF: 0.00296 AC: 76 AN: 25706

American (AMR) AF: 0.0143 AC: 518 AN: 36112

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 240 AN: 21864

East Asian (EAS) AF: 0.0462 AC: 1263 AN: 27314

South Asian (SAS) AF: 0.0193 AC: 1308 AN: 67612

European-Finnish (FIN) AF: 0.00839 AC: 381 AN: 45434

Middle Eastern (MID) AF: 0.0108 AC: 51 AN: 4706

European-Non Finnish (NFE) AF: 0.0168 AC: 14864 AN: 885494

Other (OTH) AF: 0.0166 AC: 815 AN: 48988

⚠️ 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: 0.000261 AC: 39 AN: 149444 Hom.: 0 Cov.: 0 AF XY: 0.000220 AC XY: 16 AN XY: 72798

African (AFR) AF: 0.00 AC: 0 AN: 41042

American (AMR) AF: 0.000470 AC: 7 AN: 14888

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3432

East Asian (EAS) AF: 0.00237 AC: 12 AN: 5056

South Asian (SAS) AF: 0.000854 AC: 4 AN: 4684

European-Finnish (FIN) AF: 0.000404 AC: 4 AN: 9910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67170

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0182 Hom.: 1207

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.69
Mutation Taster		=99/1	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: rs36014994; hg19: chr1-235826382; COSMIC: COSV67707814;