Variant 9-127612413-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_003165.6(STXBP1):c.10A>G(p.Ile4Val) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STXBP1
NM_003165.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.680

Variant links:

Genes affected

STXBP1 (HGNC:11444): (syntaxin binding protein 1) This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

STXBP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_003165.6

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, STXBP1

BP4

Computational evidence support a benign effect (MetaRNN=0.17503193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_003165.6 linkuse as main transcript	c.10A>G	p.Ile4Val	missense_variant	1/20	ENST00000373302.8
STXBP1	NM_001032221.6 linkuse as main transcript	c.10A>G	p.Ile4Val	missense_variant	1/19	ENST00000373299.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373302.8 linkuse as main transcript	c.10A>G	p.Ile4Val	missense_variant	1/20	1	NM_003165.6	P3	P61764-2
STXBP1	ENST00000373299.5 linkuse as main transcript	c.10A>G	p.Ile4Val	missense_variant	1/19	1	NM_001032221.6	A1	P61764-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1445104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718800

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.67

T;T;T;T;.

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;.;.;N;.

MutationTaster

Benign

0.94

N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.0

N;.;.;N;.

REVEL

Benign

0.050

Sift

Benign

0.11

T;.;.;T;.

Sift4G

Benign

0.35

T;.;.;T;.

Polyphen

0.0020

B;.;.;B;.

Vest4

0.20

MutPred

0.35

Gain of disorder (P = 0.1003);Gain of disorder (P = 0.1003);Gain of disorder (P = 0.1003);Gain of disorder (P = 0.1003);Gain of disorder (P = 0.1003);

MVP

0.22

MPC

1.1

ClinPred

0.10

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.059

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over