rs121918319

Variant names:

• chr9-127676722-T-A
• rs121918319
• NM_003165.6:c.1328T>A

Your query was ambiguous. Multiple possible variants found:

• chr9-127676722-T-A
• chr9-127676722-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_003165.6(STXBP1):​c.1328T>A​(p.Met443Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. M443V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66
• 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: Likely_pathogenic. The variant received 8 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, 11 uncertain in NM_003165.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127676722-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6728.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.1328T>A	p.Met443Lys	missense_variant	Exon 15 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1328T>A	p.Met443Lys	missense_variant	Exon 15 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1328T>A	p.Met443Lys	missense_variant	Exon 15 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.1328T>A	p.Met443Lys	missense_variant	Exon 15 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

Apr 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 443 of the STXBP1 protein (p.Met443Lys). This variant has not been reported in the literature in individuals affected with STXBP1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STXBP1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T;.;T;.;T;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.;M
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	.;.;D;.;.;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0060	.;.;D;.;.;.;D
Sift4G	Uncertain	0.039	.;.;D;.;.;.;D
Polyphen		0.87, 0.89	.;.;P;.;.;.;P
Vest4		0.99, 0.99
MutPred		0.71		.;.;Gain of ubiquitination at M443 (P = 0.0138);Gain of ubiquitination at M443 (P = 0.0138);Gain of ubiquitination at M443 (P = 0.0138);.;Gain of ubiquitination at M443 (P = 0.0138);
MVP		0.85
MPC		1.8
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.85
gMVP		1.0
Mutation Taster		=13/87	disease causing

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

dbSNP: rs121918319; hg19: chr9-130439001;