9-127612413-A-G

Position:

• chr9-127612413-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.680

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]

ACMG classification

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, 7 uncertain in NM_003165.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STXBP1. . Gene score misZ 4.263 (greater than the threshold 3.09). Trascript score misZ 5.8329 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant non-syndromic intellectual disability, Dravet syndrome, undetermined early-onset epileptic encephalopathy, autism spectrum disorder, developmental and epileptic encephalopathy, West syndrome, atypical Rett syndrome, developmental and epileptic encephalopathy, 4.
• 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	c.10A>G	p.Ile4Val	missense_variant	1/20	ENST00000373302.8
STXBP1	NM_001032221.6	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	c.10A>G	p.Ile4Val	missense_variant	1/20	1	NM_003165.6	P3
STXBP1	ENST00000373299.5	c.10A>G	p.Ile4Val	missense_variant	1/19	1	NM_001032221.6	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445104 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.0017	.;T;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.67	T;T;T;T;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;.;N;.
MutationTaster	Benign	0.94	N;N
PrimateAI	Pathogenic	0.82	D
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	T
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.

Other links and lift over

hg19: chr9-130374692;