1-235800337-T-G

Variant names:

• chr1-235800337-T-G
• rs74641549
• NM_000081.4:c.3989A>C

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.3989A>C​(p.Asp1330Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,587,506 control chromosomes in the GnomAD database, including 648 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1330G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.037 (347 hom., cov: 29)
  • Exomes 𝑓: 0.0039 (301 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.179
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016427338).
• BP6: Variant 1-235800337-T-G is Benign according to our data. Variant chr1-235800337-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254920.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.3989A>C	p.Asp1330Ala	missense	Exon 10 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.3989A>C	p.Asp1330Ala	missense	Exon 10 of 53	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.3989A>C	p.Asp1330Ala	missense	Exon 10 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000465349.5	TSL:1	n.4540A>C		non_coding_transcript_exon	Exon 10 of 12
	LYST	ENST00000489585.5	TSL:1	n.3989A>C		non_coding_transcript_exon	Exon 10 of 23	ENSP00000513166.1	Q99698-2

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5619 AN: 151970 Hom.: 346 Cov.: 29

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: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00991 AC: 2486 AN: 250804 AF XY: 0.00751

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.00558

GnomAD4 exome AF: 0.00390 AC: 5598 AN: 1435418 Hom.: 301 Cov.: 26 AF XY: 0.00335 AC XY: 2400 AN XY: 715734

African (AFR) AF: 0.130 AC: 4261 AN: 32820

American (AMR) AF: 0.00736 AC: 329 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25946

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39502

South Asian (SAS) AF: 0.000292 AC: 25 AN: 85670

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53384

Middle Eastern (MID) AF: 0.00839 AC: 48 AN: 5720

European-Non Finnish (NFE) AF: 0.000314 AC: 342 AN: 1088244

Other (OTH) AF: 0.00987 AC: 587 AN: 59460

GnomAD4 genome AF: 0.0371 AC: 5639 AN: 152088 Hom.: 347 Cov.: 29 AF XY: 0.0351 AC XY: 2613 AN XY: 74350

African (AFR) AF: 0.129 AC: 5339 AN: 41448

American (AMR) AF: 0.0140 AC: 213 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68018

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0136 Hom.: 239

Bravo AF: 0.0432

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.117 AC: 515

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0122 AC: 1482

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	0.045
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.73
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.014	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.18
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.11
Sift	Benign	0.84	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.096
ClinPred		0.0026	T
GERP RS		4.6
Varity_R		0.044
gMVP		0.095
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74641549; hg19: chr1-235963637;