rs9803890

Variant names:

• chr1-235801123-C-T
• rs9803890
• NM_000081.4:c.3713-26G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000081.4(LYST):​c.3713-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00803 in 1,325,518 control chromosomes in the GnomAD database, including 614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (342 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (272 hom.)
• Consequence: LYST NM_000081.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.966
• 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: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• attenuated Chédiak-Higashi syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-235801123-C-T is Benign according to our data. Variant chr1-235801123-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.3713-26G>A		intron_variant	Intron 8 of 52	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.3713-26G>A		intron_variant	Intron 8 of 52	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5611 AN: 152100 Hom.: 341 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00987 AC: 2433 AN: 246442 AF XY: 0.00761

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.00646

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000518

Gnomad NFE exome AF: 0.000552

Gnomad OTH exome AF: 0.00564

GnomAD4 exome AF: 0.00428 AC: 5018 AN: 1173300 Hom.: 272 Cov.: 17 AF XY: 0.00364 AC XY: 2173 AN XY: 597752

African (AFR) AF: 0.134 AC: 3774 AN: 28064

American (AMR) AF: 0.00746 AC: 331 AN: 44362

Ashkenazi Jewish (ASJ) AF: 0.0000409 AC: 1 AN: 24434

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38246

South Asian (SAS) AF: 0.000311 AC: 25 AN: 80466

European-Finnish (FIN) AF: 0.0000796 AC: 4 AN: 50258

Middle Eastern (MID) AF: 0.00843 AC: 44 AN: 5220

European-Non Finnish (NFE) AF: 0.000337 AC: 287 AN: 851288

Other (OTH) AF: 0.0108 AC: 551 AN: 50962

GnomAD4 genome AF: 0.0370 AC: 5631 AN: 152218 Hom.: 342 Cov.: 31 AF XY: 0.0350 AC XY: 2608 AN XY: 74426

African (AFR) AF: 0.128 AC: 5332 AN: 41524

American (AMR) AF: 0.0139 AC: 213 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67996

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.0144 Hom.: 47

Bravo AF: 0.0431

Asia WGS AF: 0.0130 AC: 44 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.8
DANN	Benign	0.68
PhyloP100		0.97
Mutation Taster		=99/1	polymorphism (auto)

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: rs9803890; hg19: chr1-235964423;