chr1-235702886-C-T

Variant names:

• chr1-235702886-C-T
• rs148409403
• NM_000081.4:c.10235G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_000081.4(LYST):​c.10235G>A​(p.Arg3412His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000905 in 1,614,148 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3412C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (2 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 7.57
• Publications: 13 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

ENSG00000296841 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29302818).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000703 (107/152276) while in subpopulation NFE AF = 0.00132 (90/68020). AF 95% confidence interval is 0.0011. There are 0 homozygotes in GnomAd4. There are 48 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
• BS2: High Homozygotes in GnomAdExome4 at 2 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.10235G>A	p.Arg3412His	missense	Exon 45 of 53	NP_000072.2	Q99698-1
	LYST	NM_001301365.1		c.10235G>A	p.Arg3412His	missense	Exon 45 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.10235G>A	p.Arg3412His	missense	Exon 45 of 53	ENSP00000374443.2	Q99698-1
	LYST	ENST00000697235.1		c.785G>A	p.Arg262His	missense	Exon 7 of 15	ENSP00000513202.1	A0A8V8TL78
	LYST	ENST00000462376.2	TSL:4	n.1645G>A		non_coding_transcript_exon	Exon 3 of 10

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000676 AC: 170 AN: 251326 AF XY: 0.000780

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000926 AC: 1353 AN: 1461872 Hom.: 2 Cov.: 32 AF XY: 0.000932 AC XY: 678 AN XY: 727236

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00107 AC: 1187 AN: 1111990

Other (OTH) AF: 0.000745 AC: 45 AN: 60396

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74448

African (AFR) AF: 0.000168 AC: 7 AN: 41552

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000988 Hom.: 0

Bravo AF: 0.000672

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.00131

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.2	L
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.79
ClinPred		0.16	T
GERP RS		5.4
Varity_R		0.43
gMVP		0.63
Mutation Taster		=51/49	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: rs148409403; hg19: chr1-235866186; COSMIC: COSV67702995;