1-235663082-TAAAA-TAA

Variant names:

• chr1-235663082-TAA-T
• rs36014994
• NM_000081.4:c.11268-6_11268-5delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000081.4(LYST):​c.11268-6_11268-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,314,560 control chromosomes in the GnomAD database, including 22 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (14 hom., cov: 0)
  • Exomes 𝑓: 0.012 (8 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-235663082-TAA-T is Benign according to our data. Variant chr1-235663082-TAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00552 (824/149400) while in subpopulation AFR AF = 0.0174 (715/41034). AF 95% confidence interval is 0.0164. There are 14 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.11268-6_11268-5delTT		splice_region intron	N/A	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.11268-6_11268-5delTT		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.11268-6_11268-5delTT		splice_region intron	N/A	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697235.1		c.1818-6_1818-5delTT		splice_region intron	N/A	ENSP00000513202.1	A0A8V8TL78
	LYST	ENST00000462376.2	TSL:4	n.3087-6_3087-5delTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 822 AN: 149314 Hom.: 14 Cov.: 0

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.000583

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000909

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000268

Gnomad OTH AF: 0.00388

GnomAD2 exomes AF: 0.00691 AC: 1127 AN: 163066 AF XY: 0.00603

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.00672

Gnomad ASJ exome AF: 0.00608

Gnomad EAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00834

Gnomad NFE exome AF: 0.00516

Gnomad OTH exome AF: 0.00936

GnomAD4 exome AF: 0.0117 AC: 13682 AN: 1165160 Hom.: 8 AF XY: 0.0109 AC XY: 6373 AN XY: 585776

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

African (AFR) AF: 0.0506 AC: 1168 AN: 23076

American (AMR) AF: 0.00503 AC: 195 AN: 38730

Ashkenazi Jewish (ASJ) AF: 0.00823 AC: 178 AN: 21628

East Asian (EAS) AF: 0.000180 AC: 6 AN: 33368

South Asian (SAS) AF: 0.000977 AC: 75 AN: 76802

European-Finnish (FIN) AF: 0.00876 AC: 386 AN: 44070

Middle Eastern (MID) AF: 0.0111 AC: 52 AN: 4692

European-Non Finnish (NFE) AF: 0.0127 AC: 11084 AN: 873794

Other (OTH) AF: 0.0110 AC: 538 AN: 49000

⚠️ 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: 0.00552 AC: 824 AN: 149400 Hom.: 14 Cov.: 0 AF XY: 0.00558 AC XY: 406 AN XY: 72770

African (AFR) AF: 0.0174 AC: 715 AN: 41034

American (AMR) AF: 0.00477 AC: 71 AN: 14890

Ashkenazi Jewish (ASJ) AF: 0.000583 AC: 2 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4684

European-Finnish (FIN) AF: 0.000909 AC: 9 AN: 9896

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

European-Non Finnish (NFE) AF: 0.000268 AC: 18 AN: 67142

Other (OTH) AF: 0.00385 AC: 8 AN: 2080

Alfa AF: 0.0237 Hom.: 1207

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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;