rs189657766

Variant names:

• chr1-235759020-T-C
• rs189657766
• NM_000081.4:c.6833A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000081.4(LYST):​c.6833A>G​(p.Tyr2278Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Y2278Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 3.42
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048526913).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000184 (28/152282) while in subpopulation AMR AF = 0.00111 (17/15296). AF 95% confidence interval is 0.000707. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.6833A>G	p.Tyr2278Cys	missense	Exon 23 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.6833A>G	p.Tyr2278Cys	missense	Exon 23 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.6833A>G	p.Tyr2278Cys	missense	Exon 23 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697241.1		c.1265A>G	p.Tyr422Cys	missense	Exon 6 of 26	ENSP00000513206.1	A0A8V8TM69
	LYST	ENST00000461526.2	TSL:3	n.1508A>G		non_coding_transcript_exon	Exon 7 of 28	ENSP00000513165.1	A0A8V8TL52

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000128 AC: 32 AN: 250478 AF XY: 0.0000960

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64 AN XY: 727182

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000336 AC: 15 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000953 AC: 106 AN: 1111962

Other (OTH) AF: 0.000232 AC: 14 AN: 60390

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74466

African (AFR) AF: 0.000120 AC: 5 AN: 41564

American (AMR) AF: 0.00111 AC: 17 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Chédiak-Higashi syndrome (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.47	P
Vest4		0.30
MVP		0.32
ClinPred		0.047	T
GERP RS		2.5
Varity_R		0.075
gMVP		0.39
Mutation Taster		=80/20	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: rs189657766; hg19: chr1-235922320;