rs141317482

Variant names:

• chr1-235830422-G-A
• rs141317482
• NM_000081.4:c.-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-235830422-G-A
• chr1-235830422-G-C
• chr1-235830422-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000081.4(LYST):​c.-5C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00602 in 1,603,548 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (23 hom.)
• Consequence: LYST NM_000081.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.63
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 1-235830422-G-A is Benign according to our data. Variant chr1-235830422-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254905.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00375 (570/151834) while in subpopulation NFE AF = 0.00599 (407/67970). AF 95% confidence interval is 0.00551. There are 2 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	NM_000081.4	MANE Select	c.-5C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 53	NP_000072.2
	LYST	NM_000081.4	MANE Select	c.-5C>T		splice_region	Exon 3 of 53	NP_000072.2
	LYST	NM_000081.4	MANE Select	c.-5C>T		5_prime_UTR	Exon 3 of 53	NP_000072.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.-5C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 53	ENSP00000374443.2
	LYST	ENST00000468626.2	TSL:1	c.-5C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000513173.1
	LYST	ENST00000468107.5	TSL:1	c.-5C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	ENSP00000513172.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 570 AN: 151720 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00599

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00373 AC: 907 AN: 243356 AF XY: 0.00372

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00605

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00626 AC: 9089 AN: 1451714 Hom.: 23 Cov.: 29 AF XY: 0.00610 AC XY: 4405 AN XY: 722394

African (AFR) AF: 0.00118 AC: 39 AN: 32978

American (AMR) AF: 0.00192 AC: 84 AN: 43844

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 15 AN: 25946

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39538

South Asian (SAS) AF: 0.00146 AC: 124 AN: 84886

European-Finnish (FIN) AF: 0.00634 AC: 338 AN: 53298

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5730

European-Non Finnish (NFE) AF: 0.00737 AC: 8145 AN: 1105468

Other (OTH) AF: 0.00556 AC: 334 AN: 60026

GnomAD4 genome AF: 0.00375 AC: 570 AN: 151834 Hom.: 2 Cov.: 32 AF XY: 0.00341 AC XY: 253 AN XY: 74170

African (AFR) AF: 0.00128 AC: 53 AN: 41402

American (AMR) AF: 0.00243 AC: 37 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4812

European-Finnish (FIN) AF: 0.00574 AC: 60 AN: 10460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00599 AC: 407 AN: 67970

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.00404 Hom.: 3

Bravo AF: 0.00362

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		3.6
Mutation Taster		=289/11	polymorphism

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: rs141317482; hg19: chr1-235993722;