chr6-147235325-T-G

Position:

• chr6-147235325-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001127715.4(STXBP5):​c.324T>G​(p.Ile108Met) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP5 NM_001127715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3236859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP5	NM_001127715.4	c.324T>G	p.Ile108Met	missense_variant	3/28	ENST00000321680.11	NP_001121187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP5	ENST00000321680.11	c.324T>G	p.Ile108Met	missense_variant	3/28	5	NM_001127715.4	ENSP00000321826.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The c.324T>G (p.I108M) alteration is located in exon 3 (coding exon 3) of the STXBP5 gene. This alteration results from a T to G substitution at nucleotide position 324, causing the isoleucine (I) at amino acid position 108 to be replaced by a methionine (M). 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	Benign	0.17
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T;.;T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	.;L;L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.024	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.98, 0.94	.;D;P;.
Vest4		0.47
MutPred		0.60		Loss of catalytic residue at I108 (P = 0.0994);Loss of catalytic residue at I108 (P = 0.0994);Loss of catalytic residue at I108 (P = 0.0994);Loss of catalytic residue at I108 (P = 0.0994);
MVP		0.13
MPC		0.77
ClinPred		0.73	D
GERP RS		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.37

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: rs1359652788; hg19: chr6-147556461;