7-73702846-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_004603.4(STX1A):c.677A>G(p.Gln226Arg) variant causes a missense, splice region 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. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STX1A NM_004603.4 missense, splice_region
• Scores: Splicing: ADA: 0.9785
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

Genes affected

STX1A (HGNC:11433): (syntaxin 1A) This gene encodes a member of the syntaxin superfamily. Syntaxins are nervous system-specific proteins implicated in the docking of synaptic vesicles with the presynaptic plasma membrane. Syntaxins possess a single C-terminal transmembrane domain, a SNARE [Soluble NSF (N-ethylmaleimide-sensitive fusion protein)-Attachment protein REceptor] domain (known as H3), and an N-terminal regulatory domain (Habc). Syntaxins bind synaptotagmin in a calcium-dependent fashion and interact with voltage dependent calcium and potassium channels via the C-terminal H3 domain. This gene product is a key molecule in ion channel regulation and synaptic exocytosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Syntaxin-1A (size 287) in uniprot entity STX1A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004603.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-73702846-T-C is Pathogenic according to our data. Variant chr7-73702846-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1679131.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STX1A	NM_004603.4	c.677A>G	p.Gln226Arg	missense_variant, splice_region_variant	8/10	ENST00000222812.8
STX1A	XM_047420777.1	c.677A>G	p.Gln226Arg	missense_variant	8/9
STX1A	NM_001165903.2	c.677A>G	p.Gln226Arg	missense_variant, splice_region_variant	8/10
STX1A	XM_047420778.1	c.677A>G	p.Gln226Arg	missense_variant, splice_region_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STX1A	ENST00000222812.8	c.677A>G	p.Gln226Arg	missense_variant, splice_region_variant	8/10	1	NM_004603.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Seizure;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, University of Leipzig Medical Center

Apr 22, 2022

This variant was identified as de novo. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.0	H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D;D;D;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.96
MutPred		0.87		Gain of phosphorylation at S225 (P = 0.091);Gain of phosphorylation at S225 (P = 0.091);Gain of phosphorylation at S225 (P = 0.091);Gain of phosphorylation at S225 (P = 0.091);
MVP		0.96
MPC		2.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.69
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.89
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-73117176;