NM_000081.4:c.7870C>T

Variant names:

• chr1-235746438-G-A
• rs150306354
• NM_000081.4:c.7870C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000081.4(LYST):​c.7870C>T​(p.Arg2624Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,613,734 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2624Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (17 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.29
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051336676).
• BP6: Variant 1-235746438-G-A is Benign according to our data. Variant chr1-235746438-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 454488.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0027 (411/152166) while in subpopulation NFE AF = 0.00435 (296/68004). AF 95% confidence interval is 0.00394. There are 1 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.7870C>T	p.Arg2624Trp	missense	Exon 29 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.7870C>T	p.Arg2624Trp	missense	Exon 29 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.7870C>T	p.Arg2624Trp	missense	Exon 29 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697241.1		c.2350C>T	p.Arg784Trp	missense	Exon 13 of 26	ENSP00000513206.1	A0A8V8TM69
	LYST	ENST00000461526.2	TSL:3	n.2545C>T		non_coding_transcript_exon	Exon 13 of 28	ENSP00000513165.1	A0A8V8TL52

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00680

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00269 AC: 675 AN: 251312 AF XY: 0.00270

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00541

Gnomad NFE exome AF: 0.00397

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00351 AC: 5125 AN: 1461568 Hom.: 17 Cov.: 31 AF XY: 0.00342 AC XY: 2487 AN XY: 727088

African (AFR) AF: 0.000359 AC: 12 AN: 33462

American (AMR) AF: 0.000537 AC: 24 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00159 AC: 137 AN: 86248

European-Finnish (FIN) AF: 0.00631 AC: 337 AN: 53414

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.00395 AC: 4396 AN: 1111784

Other (OTH) AF: 0.00318 AC: 192 AN: 60378

GnomAD4 genome AF: 0.00270 AC: 411 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.00304 AC XY: 226 AN XY: 74406

African (AFR) AF: 0.000578 AC: 24 AN: 41504

American (AMR) AF: 0.000654 AC: 10 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

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

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00680 AC: 72 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00435 AC: 296 AN: 68004

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00347 Hom.: 3

Bravo AF: 0.00209

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00277 AC: 336

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.051	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.51
ClinPred		0.015	T
GERP RS		3.4
Varity_R		0.34
gMVP		0.54
Mutation Taster		=61/39	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: rs150306354; hg19: chr1-235909738; COSMIC: COSV67715039; COSMIC: COSV67715039;