chr1-235788844-C-T

Variant names:

• chr1-235788844-C-T
• rs992094713
• NM_000081.4:c.4545G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000081.4(LYST):​c.4545G>A​(p.Glu1515Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LYST NM_000081.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001596
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0620
• Publications: 0 publications found

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]

LYST Gene-Disease associations (from GenCC):

• Chediak-Higashi syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• attenuated Chédiak-Higashi syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21504375).
• BP6: Variant 1-235788844-C-T is Benign according to our data. Variant chr1-235788844-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2121089.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.062 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.4545G>A	p.Glu1515Glu	splice_region_variant, synonymous_variant	Exon 13 of 53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.4545G>A	p.Glu1515Glu	splice_region_variant, synonymous_variant	Exon 13 of 53	5	NM_000081.4	ENSP00000374443.2
LYST	ENST00000489585.5	n.4545G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 23	1		ENSP00000513166.1
LYST	ENST00000492844.1	n.5G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
LYST	ENST00000697178.1	n.4118G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 52			ENSP00000513163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chédiak-Higashi syndrome Benign:1

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.86
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.062
Sift4G	Benign	1.0	T
Vest4		0.066
MVP		0.54
ClinPred		0.030	T
GERP RS		-5.0
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs992094713; hg19: chr1-235952144;