chr1-108793649-T-G

Variant names:

• chr1-108793649-T-G
• NM_007269.4:c.1029+2T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_007269.4(STXBP3):​c.1029+2T>G variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: STXBP3 NM_007269.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.86
• Publications: 0 publications found

Genes affected

STXBP3 (HGNC:11446): (syntaxin binding protein 3) Enables syntaxin binding activity. Involved in negative regulation of calcium ion-dependent exocytosis; neutrophil degranulation; and platelet aggregation. Located in cytosol; plasma membrane; and secretory granule. Is active in presynapse. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.037099496 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-108793649-T-G is Pathogenic according to our data. Variant chr1-108793649-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1879089.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP3	NM_007269.4	c.1029+2T>G		splice_donor_variant, intron_variant	Intron 12 of 18	ENST00000370008.4	NP_009200.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP3	ENST00000370008.4	c.1029+2T>G		splice_donor_variant, intron_variant	Intron 12 of 18	1	NM_007269.4	ENSP00000359025.3
STXBP3	ENST00000495245.1	n.*18T>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STXBP3: PM2, PS2:Moderate, PVS1:Moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.9
GERP RS		5.2
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -2

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

Other links and lift over

hg19: chr1-109336271;