6-147314277-A-G

Position:

• chr6-147314277-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127715.4(STXBP5):​c.1307A>G​(p.Asn436Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 1,599,470 control chromosomes in the GnomAD database, including 229,177 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (19056 hom., cov: 30)
  • Exomes 𝑓: 0.53 (210121 hom.)
• Consequence: STXBP5 NM_001127715.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.7267804E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP5	NM_001127715.4	c.1307A>G	p.Asn436Ser	missense_variant	13/28	ENST00000321680.11	NP_001121187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP5	ENST00000321680.11	c.1307A>G	p.Asn436Ser	missense_variant	13/28	5	NM_001127715.4	ENSP00000321826	A1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75400 AN: 151342 Hom.: 19046 Cov.: 30

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.505

GnomAD3 exomes AF: 0.506 AC: 127111 AN: 250960 Hom.: 32926 AF XY: 0.509 AC XY: 69037 AN XY: 135764

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.532

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.515

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.520

GnomAD4 exome AF: 0.534 AC: 773926 AN: 1448010 Hom.: 210121 Cov.: 37 AF XY: 0.534 AC XY: 384938 AN XY: 721084

Gnomad4 AFR exome AF: 0.440

Gnomad4 AMR exome AF: 0.535

Gnomad4 ASJ exome AF: 0.535

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.516

Gnomad4 FIN exome AF: 0.505

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.498 AC: 75449 AN: 151460 Hom.: 19056 Cov.: 30 AF XY: 0.494 AC XY: 36555 AN XY: 73944

Gnomad4 AFR AF: 0.442

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.274

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.493

Gnomad4 NFE AF: 0.540

Gnomad4 OTH AF: 0.502

Alfa AF: 0.527 Hom.: 18471

Bravo AF: 0.499

TwinsUK AF: 0.553 AC: 2052

ALSPAC AF: 0.546 AC: 2103

ESP6500AA AF: 0.432 AC: 1902

ESP6500EA AF: 0.542 AC: 4659

ExAC AF: 0.506 AC: 61396

Asia WGS AF: 0.428 AC: 1486 AN: 3476

EpiCase AF: 0.545

EpiControl AF: 0.552

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.62
DEOGEN2	Benign	0.051	.;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.00037	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N;N
MutationTaster	Benign	0.86	P;P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.68	N;N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.044
MPC		0.39
ClinPred		0.0084	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1039084; hg19: chr6-147635413; COSMIC: COSV51649455;