rs1063128

Variant names:

• chr1-235809567-T-C
• rs1063128
• NM_000081.4:c.1251A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000081.4(LYST):​c.1251A>G​(p.Gln417Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,613,380 control chromosomes in the GnomAD database, including 124,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13179 hom., cov: 31)
  • Exomes 𝑓: 0.38 (111264 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.0510

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-235809567-T-C is Benign according to our data. Variant chr1-235809567-T-C is described in ClinVar as [Benign]. Clinvar id is 254910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.051 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.1251A>G	p.Gln417Gln	synonymous_variant	Exon 5 of 53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.1251A>G	p.Gln417Gln	synonymous_variant	Exon 5 of 53	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61533 AN: 151790 Hom.: 13165 Cov.: 31

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.0623

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.394

GnomAD3 exomes AF: 0.345 AC: 86432 AN: 250608 Hom.: 16514 AF XY: 0.339 AC XY: 45958 AN XY: 135486

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.0588

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.382 AC: 558950 AN: 1461472 Hom.: 111264 Cov.: 42 AF XY: 0.377 AC XY: 274165 AN XY: 727034

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.0857

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.435

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.367

GnomAD4 genome AF: 0.405 AC: 61595 AN: 151908 Hom.: 13179 Cov.: 31 AF XY: 0.398 AC XY: 29561 AN XY: 74216

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.360

Gnomad4 EAS AF: 0.0625

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.434

Gnomad4 NFE AF: 0.408

Gnomad4 OTH AF: 0.391

Alfa AF: 0.403 Hom.: 16102

Bravo AF: 0.402

Asia WGS AF: 0.156 AC: 546 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.400

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Chédiak-Higashi syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.9
DANN	Benign	0.28

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: rs1063128; hg19: chr1-235972867; COSMIC: COSV67705101;