1-235702714-T-C

Variant names:

• chr1-235702714-T-C
• rs17615059
• NM_000081.4:c.10374+33A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000081.4(LYST):​c.10374+33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,562,692 control chromosomes in the GnomAD database, including 808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (46 hom., cov: 32)
  • Exomes 𝑓: 0.030 (762 hom.)
• Consequence: LYST NM_000081.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.462
• Publications: 4 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

ENSG00000296841 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-235702714-T-C is Benign according to our data. Variant chr1-235702714-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0217 (3305/152270) while in subpopulation NFE AF = 0.0339 (2303/68014). AF 95% confidence interval is 0.0327. There are 46 homozygotes in GnomAd4. There are 1511 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 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.10374+33A>G		intron	N/A	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.10374+33A>G		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.10374+33A>G		intron	N/A	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697235.1		c.924+33A>G		intron	N/A	ENSP00000513202.1	A0A8V8TL78
	LYST	ENST00000462376.2	TSL:4	n.1784+33A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3310 AN: 152152 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0227 AC: 5684 AN: 250188 AF XY: 0.0237

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0444

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0341

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0305 AC: 42962 AN: 1410422 Hom.: 762 Cov.: 25 AF XY: 0.0297 AC XY: 20951 AN XY: 704894

African (AFR) AF: 0.00514 AC: 167 AN: 32468

American (AMR) AF: 0.0125 AC: 559 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0448 AC: 1156 AN: 25776

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39440

South Asian (SAS) AF: 0.0110 AC: 937 AN: 85236

European-Finnish (FIN) AF: 0.0212 AC: 1130 AN: 53298

Middle Eastern (MID) AF: 0.0237 AC: 134 AN: 5646

European-Non Finnish (NFE) AF: 0.0349 AC: 37178 AN: 1065246

Other (OTH) AF: 0.0290 AC: 1698 AN: 58642

GnomAD4 genome AF: 0.0217 AC: 3305 AN: 152270 Hom.: 46 Cov.: 32 AF XY: 0.0203 AC XY: 1511 AN XY: 74454

African (AFR) AF: 0.00614 AC: 255 AN: 41560

American (AMR) AF: 0.0188 AC: 288 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0484 AC: 168 AN: 3468

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

South Asian (SAS) AF: 0.00789 AC: 38 AN: 4818

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0339 AC: 2303 AN: 68014

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.0295 Hom.: 116

Bravo AF: 0.0210

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.9
DANN	Benign	0.78
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs17615059; hg19: chr1-235866014;