rs797046016

Positions:

• chr9-127675924-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The ENST00000373299.5(STXBP1):​c.1231T>C​(p.Tyr411His) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 ENST00000373299.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000373299.5
• 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 5.8379 (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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.1231T>C	p.Tyr411His	missense_variant	14/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1231T>C	p.Tyr411His	missense_variant	14/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1231T>C	p.Tyr411His	missense_variant	14/20	1	NM_003165.6	ENSP00000362399	P3
STXBP1	ENST00000373299.5	c.1231T>C	p.Tyr411His	missense_variant	14/19	1	NM_001032221.6	ENSP00000362396	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 25, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;.;T;.;T;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.7	.;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.3	.;.;D;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.013	.;.;D;.;.;.;D
Sift4G	Uncertain	0.017	.;.;D;.;.;.;D
Polyphen		0.86, 0.89	.;.;P;.;.;.;P
Vest4		0.81, 0.81
MutPred		0.72		.;.;Loss of catalytic residue at Y411 (P = 0.005);Loss of catalytic residue at Y411 (P = 0.005);Loss of catalytic residue at Y411 (P = 0.005);.;Loss of catalytic residue at Y411 (P = 0.005);
MVP		0.85
MPC		2.8
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.94

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: rs797046016; hg19: chr9-130438203;