9-127612414-T-G

Variant names:

• chr9-127612414-T-G
• NM_003165.6:c.11T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001032221.6(STXBP1):​c.11T>G​(p.Ile4Ser) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: STXBP1 NM_001032221.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0420
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_001032221.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2032347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.11T>G	p.Ile4Ser	missense_variant	Exon 1 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.11T>G	p.Ile4Ser	missense_variant	Exon 1 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.11T>G	p.Ile4Ser	missense_variant	Exon 1 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.11T>G	p.Ile4Ser	missense_variant	Exon 1 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 29, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.0014	.;T;.;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T;T;T;T;.
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.42	N;.;.;N;.
PhyloP100		0.042
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.050	N;.;.;N;.
REVEL	Benign	0.18
Sift	Benign	0.31	T;.;.;T;.
Sift4G	Benign	0.53	T;.;.;T;.
Polyphen		0.0	B;.;.;B;.
Vest4		0.32
MutPred		0.40		Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);Gain of disorder (P = 0.0062);
MVP		0.33
MPC		1.7
ClinPred		0.21	T
GERP RS		2.7
PromoterAI		-0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.72
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

hg19: chr9-130374693;