chr1-235757274-C-T

Variant names:

• chr1-235757274-C-T
• rs111764031
• NM_000081.4:c.7059+7G>A

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.7059+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,601,264 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (10 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003201
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.159
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-235757274-C-T is Benign according to our data. Variant chr1-235757274-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00543 (823/151552) while in subpopulation AFR AF = 0.0176 (726/41272). AF 95% confidence interval is 0.0165. There are 17 homozygotes in GnomAd4. There are 393 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.7059+7G>A		splice_region intron	N/A	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.7059+7G>A		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.7059+7G>A		splice_region intron	N/A	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697241.1		c.1491+7G>A		splice_region intron	N/A	ENSP00000513206.1	A0A8V8TM69
	LYST	ENST00000461526.2	TSL:3	n.1734+7G>A		splice_region intron	N/A	ENSP00000513165.1	A0A8V8TL52

Frequencies

GnomAD3 genomes AF: 0.00542 AC: 821 AN: 151434 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00461

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00338

GnomAD2 exomes AF: 0.00151 AC: 379 AN: 250572 AF XY: 0.00120

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000717 AC: 1040 AN: 1449712 Hom.: 10 Cov.: 28 AF XY: 0.000666 AC XY: 481 AN XY: 721990

African (AFR) AF: 0.0192 AC: 636 AN: 33186

American (AMR) AF: 0.00161 AC: 72 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 27 AN: 26010

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39530

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00559 AC: 32 AN: 5722

European-Non Finnish (NFE) AF: 0.000143 AC: 157 AN: 1101640

Other (OTH) AF: 0.00174 AC: 104 AN: 59884

GnomAD4 genome AF: 0.00543 AC: 823 AN: 151552 Hom.: 17 Cov.: 32 AF XY: 0.00531 AC XY: 393 AN XY: 73992

African (AFR) AF: 0.0176 AC: 726 AN: 41272

American (AMR) AF: 0.00460 AC: 70 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67892

Other (OTH) AF: 0.00334 AC: 7 AN: 2094

Alfa AF: 0.00302 Hom.: 3

Bravo AF: 0.00606

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.1
DANN	Benign	0.52
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0
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: rs111764031; hg19: chr1-235920574;