1-235752126-T-C

Position:

• chr1-235752126-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000081.4(LYST):​c.7506A>G​(p.Gln2502=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000829 in 1,612,156 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 0.226

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-235752126-T-C is Benign according to our data. Variant chr1-235752126-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254939.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=2}. Variant chr1-235752126-T-C is described in Lovd as [Benign]. Variant chr1-235752126-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.226 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00108 (165/152266) while in subpopulation AMR AF= 0.00399 (61/15296). AF 95% confidence interval is 0.00319. There are 1 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYST	NM_000081.4	c.7506A>G	p.Gln2502=	synonymous_variant	27/53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.7506A>G	p.Gln2502=	synonymous_variant	27/53	5	NM_000081.4	ENSP00000374443	P1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00117 AC: 293 AN: 250672 Hom.: 0 AF XY: 0.00128 AC XY: 173 AN XY: 135522

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000936

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.000803 AC: 1172 AN: 1459890 Hom.: 2 Cov.: 29 AF XY: 0.000862 AC XY: 626 AN XY: 726352

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00613

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000589

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74450

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000868

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00118

Asia WGS AF: 0.000578 AC: 2 AN: 3472

EpiCase AF: 0.00175

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Likely 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	Mar 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Chédiak-Higashi syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	LYST: BP4, BP7 -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.2
DANN	Benign	0.41

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: rs140434436; hg19: chr1-235915426;