rs34830702

chr9-127660033-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 5P and 13B. PM1 PM5 PP2 BP4_Strong BP6 BS1 BS2

The NM_003165.6(STXBP1):c.250G>A(p.Val84Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000312 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V84D) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.56

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 Benign. Variant got -8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_003165.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127660034-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 6729.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, STXBP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.010553926).
• BP6: Variant 9-127660033-G-A is Benign according to our data. Variant chr9-127660033-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207404.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000342 (52/152070) while in subpopulation SAS AF= 0.00104 (5/4804). AF 95% confidence interval is 0.00041. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_003165.6	c.250G>A	p.Val84Ile	missense_variant	5/20	ENST00000373302.8
STXBP1	NM_001032221.6	c.250G>A	p.Val84Ile	missense_variant	5/19	ENST00000373299.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373302.8	c.250G>A	p.Val84Ile	missense_variant	5/20	1	NM_003165.6	P3
STXBP1	ENST00000373299.5	c.250G>A	p.Val84Ile	missense_variant	5/19	1	NM_001032221.6	A1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 151952 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000628 AC: 158 AN: 251472 Hom.: 0 AF XY: 0.000589 AC XY: 80 AN XY: 135910

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.000331 AC XY: 241 AN XY: 727228

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00983

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152070 Hom.: 0 Cov.: 31 AF XY: 0.000309 AC XY: 23 AN XY: 74320

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000494 Hom.: 0

Bravo AF: 0.000310

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2016

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

STXBP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
Polyphen		0.92, 0.94	.;.;.;P;.;.;.;.;.;P;.
Vest4		0.22, 0.22
MVP		0.48
MPC		1.7
ClinPred		0.019	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34830702; hg19: chr9-130422312; COSMIC: COSV64815509; COSMIC: COSV64815509;