rs34702903

Variant names:

• chr1-235731066-A-C
• rs34702903
• NM_000081.4:c.8913T>G

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.8913T>G​(p.Asn2971Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,613,680 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. N2971S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (15 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 2.21
• Publications: 10 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=0.02045229).
• BP6: Variant 1-235731066-A-C is Benign according to our data. Variant chr1-235731066-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 525179.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00259 (394/152290) while in subpopulation NFE AF = 0.00447 (304/68008). AF 95% confidence interval is 0.00406. There are 1 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 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.8913T>G	p.Asn2971Lys	missense	Exon 35 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.8913T>G	p.Asn2971Lys	missense	Exon 35 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.8913T>G	p.Asn2971Lys	missense	Exon 35 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697241.1		c.3393T>G	p.Asn1131Lys	missense	Exon 19 of 26	ENSP00000513206.1	A0A8V8TM69
	LYST	ENST00000475277.2	TSL:5	c.1008T>G	p.Asn336Lys	missense	Exon 7 of 15	ENSP00000513164.1	A0A8V8TM32

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152172 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00244 AC: 614 AN: 251384 AF XY: 0.00246

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00422 AC: 6166 AN: 1461390 Hom.: 15 Cov.: 31 AF XY: 0.00412 AC XY: 2994 AN XY: 727052

African (AFR) AF: 0.000896 AC: 30 AN: 33466

American (AMR) AF: 0.00119 AC: 53 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00521 AC: 5796 AN: 1111598

Other (OTH) AF: 0.00287 AC: 173 AN: 60368

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152290 Hom.: 1 Cov.: 31 AF XY: 0.00227 AC XY: 169 AN XY: 74472

African (AFR) AF: 0.00101 AC: 42 AN: 41572

American (AMR) AF: 0.00137 AC: 21 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 68008

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

Alfa AF: 0.00389 Hom.: 3

Bravo AF: 0.00275

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00216 AC: 262

EpiCase AF: 0.00485

EpiControl AF: 0.00468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.096
Sift	Benign	0.66	T
Sift4G	Uncertain	0.054	T
Polyphen		0.90	P
Vest4		0.74
MutPred		0.41		Gain of methylation at N2971 (P = 0.0065)
MVP		0.66
ClinPred		0.030	T
GERP RS		2.1
Varity_R		0.16
gMVP		0.67
Mutation Taster		=42/58	disease causing

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: rs34702903; hg19: chr1-235894366;