rs148528112

Variant names:

• chr6-147278153-A-G
• rs148528112
• NM_001127715.4:c.787A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001127715.4(STXBP5):​c.787A>G​(p.Ile263Val) variant causes a missense change. The variant allele was found at a frequency of 0.000268 in 1,612,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: STXBP5 NM_001127715.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.91
• Publications: 0 publications found

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]

ENSG00000293909 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015360326).
• BP6: Variant 6-147278153-A-G is Benign according to our data. Variant chr6-147278153-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3050222.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 223 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127715.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP5	NM_001127715.4	MANE Select	c.787A>G	p.Ile263Val	missense	Exon 8 of 28	NP_001121187.1	Q5T5C0-1
	STXBP5	NM_001394409.1		c.787A>G	p.Ile263Val	missense	Exon 8 of 27	NP_001381338.1	H0Y332
	STXBP5	NM_139244.6		c.787A>G	p.Ile263Val	missense	Exon 8 of 26	NP_640337.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP5	ENST00000321680.11	TSL:5 MANE Select	c.787A>G	p.Ile263Val	missense	Exon 8 of 28	ENSP00000321826.6	Q5T5C0-1
	STXBP5	ENST00000367481.7	TSL:1	c.787A>G	p.Ile263Val	missense	Exon 8 of 26	ENSP00000356451.3	Q5T5C0-2
	STXBP5	ENST00000546097.5	TSL:1	c.895A>G	p.Ile299Val	missense	Exon 8 of 10	ENSP00000441479.2	F6VFW0

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000303 AC: 76 AN: 251168 AF XY: 0.000236

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000143 AC: 209 AN: 1460618 Hom.: 0 Cov.: 30 AF XY: 0.000114 AC XY: 83 AN XY: 726664

African (AFR) AF: 0.00475 AC: 159 AN: 33444

American (AMR) AF: 0.000358 AC: 16 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111184

Other (OTH) AF: 0.000315 AC: 19 AN: 60316

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74470

African (AFR) AF: 0.00474 AC: 197 AN: 41570

American (AMR) AF: 0.00111 AC: 17 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00170 Hom.: 1

Bravo AF: 0.00183

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	STXBP5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.048
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.050	N
PhyloP100		4.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.19
Sift	Benign	0.93	T
Sift4G	Benign	0.44	T
Polyphen		0.11	B
Vest4		0.44
MVP		0.093
MPC		0.42
ClinPred		0.035	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
gMVP		0.19
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148528112; hg19: chr6-147599289;