1-235770235-C-G

Position:

• chr1-235770235-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000081.4(LYST):​c.5847G>C​(p.Gln1949His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,622 control chromosomes in the GnomAD database, including 1,391 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (765 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (626 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.420

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LYST. . Trascript score misZ 4.0845 (greater than threshold 3.09). GenCC has associacion of gene with Chediak-Higashi syndrome, attenuated Chédiak-Higashi syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0012516677).
• BP6: Variant 1-235770235-C-G is Benign according to our data. Variant chr1-235770235-C-G is described in ClinVar as [Benign]. Clinvar id is 254929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.5847G>C	p.Gln1949His	missense_variant	20/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.5847G>C	p.Gln1949His	missense_variant	20/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8243 AN: 152038 Hom.: 762 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0377

GnomAD3 exomes AF: 0.0143 AC: 3581 AN: 251022 Hom.: 288 AF XY: 0.0106 AC XY: 1436 AN XY: 135662

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.00877

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00570 AC: 8334 AN: 1461466 Hom.: 626 Cov.: 31 AF XY: 0.00503 AC XY: 3660 AN XY: 727048

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000486

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0543 AC: 8269 AN: 152156 Hom.: 765 Cov.: 32 AF XY: 0.0526 AC XY: 3909 AN XY: 74378

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.0373

Alfa AF: 0.00885 Hom.: 74

Bravo AF: 0.0619

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.188 AC: 828

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.0183 AC: 2226

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chédiak-Higashi syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.73	N
MutationTaster	Benign	0.60	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.093
Sift	Benign	0.37	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.050
MutPred		0.22		Loss of helix (P = 0.0376);
ClinPred		0.00032	T
GERP RS		0.81
Varity_R		0.056
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs6665568; hg19: chr1-235933535;