9-127612432-T-A

Position:

• chr9-127612432-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_003165.6(STXBP1):​c.29T>A​(p.Val10Asp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V10V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0760

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 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_003165.6	c.29T>A	p.Val10Asp	missense_variant	1/20	ENST00000373302.8
STXBP1	NM_001032221.6	c.29T>A	p.Val10Asp	missense_variant	1/19	ENST00000373299.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373302.8	c.29T>A	p.Val10Asp	missense_variant	1/20	1	NM_003165.6	P3
STXBP1	ENST00000373299.5	c.29T>A	p.Val10Asp	missense_variant	1/19	1	NM_001032221.6	A1

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

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	0.97
DEOGEN2	Benign	0.25	.;T;.;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.0096
FATHMM_MKL	Benign	0.68	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	0.061	D
MutationAssessor	Uncertain	2.9	M;.;.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.9	D;.;.;D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.95	P;.;.;P;.
Vest4		0.69
MutPred		0.74		Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);
MVP		0.99
MPC		2.1
ClinPred		0.97	D
GERP RS		1.4
Varity_R		0.75
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs1838430536; hg19: chr9-130374711;