rs147221131

chr1-235664574-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP2 BP4_Strong BP6 BS1

The NM_000081.4(LYST):c.11086G>A(p.Val3696Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. V3696A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: LYST NM_000081.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.27

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LYST
• BP4: Computational evidence support a benign effect (MetaRNN=0.012456536).
• BP6: Variant 1-235664574-C-T is Benign according to our data. Variant chr1-235664574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr1-235664574-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000552 (84/152274) while in subpopulation NFE AF= 0.000955 (65/68030). AF 95% confidence interval is 0.000768. There are 0 homozygotes in gnomad4. There are 32 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.11086G>A	p.Val3696Ile	missense_variant	51/53	ENST00000389793.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYST	ENST00000389793.7	c.11086G>A	p.Val3696Ile	missense_variant	51/53	5	NM_000081.4	P1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000605 AC: 152 AN: 251038 Hom.: 0 AF XY: 0.000575 AC XY: 78 AN XY: 135700

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000644

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.000697 AC: 1019 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.000642 AC XY: 467 AN XY: 727222

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000795

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74460

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000780 Hom.: 0

Bravo AF: 0.000650

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000749 AC: 91

EpiCase AF: 0.00125

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2021	Reported in a proband with a fatal case of H1N1 influenza and in at least one individual from a cohort of patients with primary lateral sclerosis, but familial segregation information and further clinical information were not provided (Schulert et al., 2016; Finegan et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31325016, 26597256) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LYST: BP4 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 03, 2023

Variant summary: LYST c.11086G>A (p.Val3696Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251038 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.52 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 a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.11086G>A in individuals affected with Chediak-Higashi Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as a avriant of uncertain significance, while one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

LYST-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2023

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	0.077
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.88	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.097
Sift	Benign	0.26	T
Sift4G	Benign	0.70	T
Polyphen		0.64	P
Vest4		0.19
MVP		0.41
ClinPred		0.018	T
GERP RS		5.0
Varity_R		0.041
gMVP		0.054

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147221131; hg19: chr1-235827874; COSMIC: COSV67711106;