rs34702903

chr1-235731066-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

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. 14/21 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:6 B:4
• Conservation: PhyloP100: 2.21

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LYST
• 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 id is 525179.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=4}. Variant chr1-235731066-A-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYST	NM_000081.4	c.8913T>G	p.Asn2971Lys	missense_variant	35/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.8913T>G	p.Asn2971Lys	missense_variant	35/53	5	NM_000081.4	P1

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

GnomAD3 exomes AF: 0.00244 AC: 614 AN: 251384 Hom.: 0 AF XY: 0.00246 AC XY: 334 AN XY: 135856

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 SAS 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

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.00521

Gnomad4 OTH exome AF: 0.00287

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

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00415 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2019	Identified as a single heterozygous variant in two individuals with fatal H1N1 influenza and identified with another LYST variant in another individual with cerebellar ataxia, but limited phenotypic information was provided on these individuals (Schulert et al., 2016; Coutelier et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29482223, 26597256) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 14, 2019	- -

Chédiak-Higashi syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 30, 2022	LYST NM_000081.3 exon 35 p.Asn2971Lys (c.8913T>G): This variant has been reported in the literature in at least 1 individual with cerebellar ataxia (Coutelier 2018 PMID:29482223). This variant is present in 0.4% (580/129120) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235894366-A-C). This variant is present in ClinVar (Variation ID:525179). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2023	Variant summary: LYST c.8913T>G (p.Asn2971Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 251384 control chromosomes. The observed variant frequency is approximately 2.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome phenotype (0.0011), suggesting that the variant is benign. c.8913T>G has been reported in the literature in settings of whole exome or multigene panel testing in individuals affected with clinical features that have been reported in Chediak-Higashi Syndrome, including cerebellar ataxia, reported as a VUS with compound heterozygous genotype (e.g.Coutelier_2018), fatal H1N1, reported as a VUS in a heterozygous genotype (e.g. Schulert_2016), unspecified inherited bleeding disorder with unspecified genotype (e.g. Leinoe_2017), and unclassified neuroinflammatory disease with isolated incidence of hemiplegia and ataxia as a compound heterozygous genotype with variants in multiple neuroinflammatory genes (e.g.McCreary_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Chediak-Higashi Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29482223, 28748566, 31664448, 26597256). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 08, 2021	- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2019

- -

LYST-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
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

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: rs34702903; hg19: chr1-235894366;