1-235663082-TAAAA-TAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000081.4(LYST):​c.11268-5delT 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24874 hom., cov: 0)
  • Exomes 𝑓: 0.45 (44544 hom.)
  • Failed GnomAD Quality Control
• Consequence: LYST NM_000081.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-235663082-TA-T is Benign according to our data. Variant chr1-235663082-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

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.11268-5delT		splice_region intron	N/A	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.11268-5delT		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.11268-5delT		splice_region intron	N/A	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697235.1		c.1818-5delT		splice_region intron	N/A	ENSP00000513202.1	A0A8V8TL78
	LYST	ENST00000462376.2	TSL:4	n.3087-5delT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.553 AC: 82566 AN: 149220 Hom.: 24831 Cov.: 0

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.0495

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.508 AC: 82886 AN: 163066 AF XY: 0.508

Gnomad AFR exome AF: 0.681

Gnomad AMR exome AF: 0.448

Gnomad ASJ exome AF: 0.517

Gnomad EAS exome AF: 0.239

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.512

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.451 AC: 505703 AN: 1122018 Hom.: 44544 Cov.: 0 AF XY: 0.451 AC XY: 251328 AN XY: 557718

African (AFR) AF: 0.582 AC: 14906 AN: 25598

American (AMR) AF: 0.389 AC: 12497 AN: 32128

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 9746 AN: 20776

East Asian (EAS) AF: 0.190 AC: 4370 AN: 22946

South Asian (SAS) AF: 0.315 AC: 17610 AN: 55940

European-Finnish (FIN) AF: 0.504 AC: 22250 AN: 44118

Middle Eastern (MID) AF: 0.448 AC: 2031 AN: 4536

European-Non Finnish (NFE) AF: 0.462 AC: 400966 AN: 868486

Other (OTH) AF: 0.449 AC: 21327 AN: 47490

GnomAD4 genome AF: 0.554 AC: 82650 AN: 149304 Hom.: 24874 Cov.: 0 AF XY: 0.540 AC XY: 39239 AN XY: 72718

African (AFR) AF: 0.774 AC: 31731 AN: 41020

American (AMR) AF: 0.390 AC: 5786 AN: 14854

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1667 AN: 3426

East Asian (EAS) AF: 0.0497 AC: 251 AN: 5054

South Asian (SAS) AF: 0.176 AC: 822 AN: 4678

European-Finnish (FIN) AF: 0.549 AC: 5432 AN: 9898

Middle Eastern (MID) AF: 0.504 AC: 141 AN: 280

European-Non Finnish (NFE) AF: 0.526 AC: 35295 AN: 67112

Other (OTH) AF: 0.522 AC: 1085 AN: 2078

Alfa AF: 0.430 Hom.: 1207

Bravo AF: 0.553

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Chédiak-Higashi syndrome (5)
-	-	5	not specified (5)
-	-	2	not provided (3)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: COSV67710885;