rs1060501722

Variant names:

• chr9-127678505-G-A
• rs1060501722
• NM_003165.6:c.1434G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-127678505-G-A
• chr9-127678505-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003165.6(STXBP1):​c.1434G>A​(p.Trp478*) variant causes a stop gained 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STXBP1 NM_003165.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60
• Publications: 3 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127678505-G-A is Pathogenic according to our data. Variant chr9-127678505-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 407777.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.1434G>A	p.Trp478*	stop_gained	Exon 16 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1434G>A	p.Trp478*	stop_gained	Exon 16 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1434G>A	p.Trp478*	stop_gained	Exon 16 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.1434G>A	p.Trp478*	stop_gained	Exon 16 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424546 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 704610

African (AFR) AF: 0.00 AC: 0 AN: 33118

American (AMR) AF: 0.00 AC: 0 AN: 38190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.00 AC: 0 AN: 38506

South Asian (SAS) AF: 0.00 AC: 0 AN: 81010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092712

Other (OTH) AF: 0.00 AC: 0 AN: 59100

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Pathogenic:1

Jun 09, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Truncating variants in STXBP1 are known to be pathogenic. This particular truncation has been reported in the literature in an individual affected with early-onset epileptic encephalopathy (PMID: 20876469). This sequence change creates a premature translational stop signal at codon 478 (p.Trp478*) of the STXBP1 gene. It is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	41
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.
PhyloP100		9.6
PROVEAN	Benign	0.0	.;.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.
Vest4		0.0
GERP RS		5.2
PromoterAI		0.0058	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060501722; hg19: chr9-130440784;