rs12088737

Variant names:

• chr1-235664645-G-A
• rs12088737
• NM_000081.4:c.11039-24C>T

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.11039-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,613,624 control chromosomes in the GnomAD database, including 3,018 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1539 hom., cov: 31)
  • Exomes 𝑓: 0.0091 (1479 hom.)
• Consequence: LYST NM_000081.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.236
• Publications: 1 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=-0.74).
• BP6: Variant 1-235664645-G-A is Benign according to our data. Variant chr1-235664645-G-A is described in ClinVar as Benign. ClinVar VariationId is 254909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.11039-24C>T		intron_variant	Intron 50 of 52	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.11039-24C>T		intron_variant	Intron 50 of 52	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11963 AN: 152014 Hom.: 1536 Cov.: 31

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.0613

GnomAD2 exomes AF: 0.0227 AC: 5669 AN: 249812 AF XY: 0.0173

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000933

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.00906 AC: 13247 AN: 1461492 Hom.: 1479 Cov.: 32 AF XY: 0.00831 AC XY: 6041 AN XY: 727066

African (AFR) AF: 0.281 AC: 9397 AN: 33440

American (AMR) AF: 0.0155 AC: 692 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39686

South Asian (SAS) AF: 0.0141 AC: 1217 AN: 86234

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53352

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5766

European-Non Finnish (NFE) AF: 0.000609 AC: 677 AN: 1111798

Other (OTH) AF: 0.0198 AC: 1196 AN: 60374

GnomAD4 genome AF: 0.0789 AC: 12008 AN: 152132 Hom.: 1539 Cov.: 31 AF XY: 0.0761 AC XY: 5661 AN XY: 74382

African (AFR) AF: 0.270 AC: 11186 AN: 41452

American (AMR) AF: 0.0342 AC: 522 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0183 AC: 88 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68022

Other (OTH) AF: 0.0640 AC: 135 AN: 2110

Alfa AF: 0.0267 Hom.: 612

Bravo AF: 0.0916

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: 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	-0.74
CADD	Benign	5.3
DANN	Benign	0.89
PhyloP100		-0.24
Mutation Taster		=100/0	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: rs12088737; hg19: chr1-235827945;