chr6-147310224-C-T

Variant names:

• chr6-147310224-C-T
• NM_001127715.4:c.1058C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001127715.4(STXBP5):​c.1058C>T​(p.Thr353Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: STXBP5 NM_001127715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

STXBP5 (HGNC:19665): (syntaxin binding protein 5) Syntaxin 1 is a component of the 7S and 20S SNARE complexes which are involved in docking and fusion of synaptic vesicles with the presynaptic plasma membrane. This gene encodes a syntaxin 1 binding protein. In rat, a similar protein dissociates syntaxin 1 from the Munc18/n-Sec1/rbSec1 complex to form a 10S complex, an intermediate which can be converted to the 7S SNARE complex. Thus this protein is thought to be involved in neurotransmitter release by stimulating SNARE complex formation. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP5	NM_001127715.4	c.1058C>T	p.Thr353Ile	missense_variant	Exon 10 of 28	ENST00000321680.11	NP_001121187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP5	ENST00000321680.11	c.1058C>T	p.Thr353Ile	missense_variant	Exon 10 of 28	5	NM_001127715.4	ENSP00000321826.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1058C>T (p.T353I) alteration is located in exon 10 (coding exon 10) of the STXBP5 gene. This alteration results from a C to T substitution at nucleotide position 1058, causing the threonine (T) at amino acid position 353 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.70
MutPred		0.57		Loss of catalytic residue at T353 (P = 0.0438);Loss of catalytic residue at T353 (P = 0.0438);Loss of catalytic residue at T353 (P = 0.0438);
MVP		0.19
MPC		1.4
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-147631360; COSMIC: COSV51647463;