rs147756847

chr1-235759371-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000081.4(LYST):c.6482A>C(p.Glu2161Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00511 in 1,614,230 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (42 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 5.56

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LYST
• BP4: Computational evidence support a benign effect (MetaRNN=0.0030755103).
• BP6: Variant 1-235759371-T-G is Benign according to our data. Variant chr1-235759371-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254931.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=4}. Variant chr1-235759371-T-G is described in Lovd as [Benign]. Variant chr1-235759371-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00421 (641/152380) while in subpopulation AMR AF= 0.00588 (90/15306). AF 95% confidence interval is 0.0049. There are 5 homozygotes in gnomad4. There are 286 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.6482A>C	p.Glu2161Ala	missense_variant	23/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.6482A>C	p.Glu2161Ala	missense_variant	23/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 642 AN: 152262 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00476 AC: 1197 AN: 251264 Hom.: 7 AF XY: 0.00496 AC XY: 673 AN XY: 135804

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00517

Gnomad OTH exome AF: 0.00767

GnomAD4 exome AF: 0.00520 AC: 7603 AN: 1461850 Hom.: 42 Cov.: 33 AF XY: 0.00527 AC XY: 3834 AN XY: 727222

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.0354

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00289

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00692

GnomAD4 genome AF: 0.00421 AC: 641 AN: 152380 Hom.: 5 Cov.: 32 AF XY: 0.00384 AC XY: 286 AN XY: 74518

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00618 Hom.: 9

Bravo AF: 0.00468

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00428 AC: 519

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00640

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 23, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 3.3% [338/10366]; including in 7 homozygotes; https://gnomad.broadinstitute.org/variant/1-235922671-T-G?dataset=gnomad_r2_1), and in ClinVar, with several laboratories classifying it as benign or likely benign (Variation ID: 254931). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Apr 13, 2016	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LYST: BP4, BS2 -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.014	D
Polyphen		0.23	B
Vest4		0.21
MVP		0.60
ClinPred		0.036	T
GERP RS		2.8
Varity_R		0.099
gMVP		0.38

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: rs147756847; hg19: chr1-235922671; COSMIC: COSV67709603;