rs35333195

Variant names:

• chr1-235734607-C-T
• rs35333195
• NM_000081.4:c.8411G>A

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.8411G>A​(p.Gly2804Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0071 in 1,612,852 control chromosomes in the GnomAD database, including 680 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2804G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.037 (352 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (328 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.46
• Publications: 7 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, 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 (MetaRNN=0.0012811124).
• BP6: Variant 1-235734607-C-T is Benign according to our data. Variant chr1-235734607-C-T is described in ClinVar as Benign. ClinVar VariationId is 254941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

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.8411G>A	p.Gly2804Asp	missense	Exon 32 of 53	NP_000072.2
	LYST	NM_001301365.1		c.8411G>A	p.Gly2804Asp	missense	Exon 32 of 53	NP_001288294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYST	ENST00000389793.7	TSL:5 MANE Select	c.8411G>A	p.Gly2804Asp	missense	Exon 32 of 53	ENSP00000374443.2
	LYST	ENST00000697241.1		c.2891G>A	p.Gly964Asp	missense	Exon 16 of 26	ENSP00000513206.1
	LYST	ENST00000475277.2	TSL:5	c.506G>A	p.Gly169Asp	missense	Exon 4 of 15	ENSP00000513164.1

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5647 AN: 152052 Hom.: 351 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0101 AC: 2531 AN: 251142 AF XY: 0.00754

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.00651

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00396 AC: 5788 AN: 1460682 Hom.: 328 Cov.: 30 AF XY: 0.00341 AC XY: 2479 AN XY: 726628

African (AFR) AF: 0.132 AC: 4423 AN: 33436

American (AMR) AF: 0.00745 AC: 333 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86118

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53376

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5762

European-Non Finnish (NFE) AF: 0.000313 AC: 348 AN: 1111176

Other (OTH) AF: 0.0100 AC: 604 AN: 60332

GnomAD4 genome AF: 0.0372 AC: 5667 AN: 152170 Hom.: 352 Cov.: 32 AF XY: 0.0354 AC XY: 2631 AN XY: 74390

African (AFR) AF: 0.129 AC: 5367 AN: 41498

American (AMR) AF: 0.0140 AC: 214 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67984

Other (OTH) AF: 0.0213 AC: 45 AN: 2108

Alfa AF: 0.0132 Hom.: 267

Bravo AF: 0.0432

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.120 AC: 527

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0124 AC: 1506

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
PhyloP100		2.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	3.7	N
REVEL	Benign	0.090
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
ClinPred		0.0014	T
GERP RS		2.7
Varity_R		0.036
gMVP		0.18
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: rs35333195; hg19: chr1-235897907;