NM_003165.6:c.1480C>T

Variant names:

• chr9-127680175-C-T
• rs1554778810
• NM_003165.6:c.1480C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_003165.6(STXBP1):​c.1480C>T​(p.Leu494Phe) variant causes a missense change. 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 NM_003165.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.04

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the STXBP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 79 curated benign missense variants. Gene score misZ: 4.263 (above the threshold of 3.09). Trascript score misZ: 5.8329 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.1480C>T	p.Leu494Phe	missense_variant	Exon 17 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1480C>T	p.Leu494Phe	missense_variant	Exon 17 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1480C>T	p.Leu494Phe	missense_variant	Exon 17 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.1480C>T	p.Leu494Phe	missense_variant	Exon 17 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 11, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Feb 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with phenylalanine at codon 494 of the STXBP1 protein (p.Leu494Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of STXBP1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 522070). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Developmental and epileptic encephalopathy, 4 Uncertain:1

Feb 23, 2018

Centogene AG - the Rare Disease Company

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;.;T;.;T;D;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	.;.;D;.;.;.;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	.;.;D;.;.;.;D;.
Sift4G	Uncertain	0.030	.;.;D;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;D;.
Vest4		0.70, 0.71
MutPred		0.88		.;.;Gain of methylation at K493 (P = 0.0767);Gain of methylation at K493 (P = 0.0767);Gain of methylation at K493 (P = 0.0767);.;Gain of methylation at K493 (P = 0.0767);.;
MVP		0.82
MPC		2.6
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.95

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: rs1554778810; hg19: chr9-130442454;