1-235686945-C-A

Variant names:

• chr1-235686945-C-A
• rs41308172
• NM_000081.4:c.10800+4G>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.10800+4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,612,438 control chromosomes in the GnomAD database, including 50 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (44 hom.)
• Consequence: LYST NM_000081.4 splice_region, intron
• Scores: Splicing: ADA: 0.009497
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.384
• 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

ENSG00000296841 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 1-235686945-C-A is Benign according to our data. Variant chr1-235686945-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296350.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00449 (684/152328) while in subpopulation NFE AF = 0.00681 (463/68026). AF 95% confidence interval is 0.00629. There are 6 homozygotes in GnomAd4. There are 307 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.10800+4G>T		splice_region intron	N/A	NP_000072.2
	LYST	NM_001301365.1		c.10800+4G>T		splice_region intron	N/A	NP_001288294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.10800+4G>T		splice_region intron	N/A	ENSP00000374443.2
	LYST	ENST00000697235.1		c.1350+4G>T		splice_region intron	N/A	ENSP00000513202.1
	LYST	ENST00000462376.2	TSL:4	n.2210+4G>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152210 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00681

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00643 AC: 1618 AN: 251454 AF XY: 0.00617

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00676

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00669 AC: 9763 AN: 1460110 Hom.: 44 Cov.: 30 AF XY: 0.00665 AC XY: 4829 AN XY: 726498

African (AFR) AF: 0.000957 AC: 32 AN: 33444

American (AMR) AF: 0.0167 AC: 745 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 49 AN: 26118

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39668

South Asian (SAS) AF: 0.00458 AC: 395 AN: 86226

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53414

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00732 AC: 8126 AN: 1110418

Other (OTH) AF: 0.00578 AC: 349 AN: 60332

GnomAD4 genome AF: 0.00449 AC: 684 AN: 152328 Hom.: 6 Cov.: 32 AF XY: 0.00412 AC XY: 307 AN XY: 74496

African (AFR) AF: 0.00149 AC: 62 AN: 41574

American (AMR) AF: 0.00680 AC: 104 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4832

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00681 AC: 463 AN: 68026

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00658 Hom.: 5

Bravo AF: 0.00550

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00699

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Chédiak-Higashi syndrome (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		0.38
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0095
dbscSNV1_RF	Benign	0.082
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs41308172; hg19: chr1-235850245;