7-73719606-C-T

Position:

• chr7-73719606-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004603.4(STX1A):​c.26G>A​(p.Arg9His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,055,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: STX1A NM_004603.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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]

STX1A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23944762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STX1A	NM_004603.4	c.26G>A	p.Arg9His	missense_variant	1/10	ENST00000222812.8	NP_004594.1
STX1A	NM_001165903.2	c.26G>A	p.Arg9His	missense_variant	1/10		NP_001159375.1
STX1A	XM_047420777.1	c.26G>A	p.Arg9His	missense_variant	1/9		XP_047276733.1
STX1A	XM_047420778.1	c.26G>A	p.Arg9His	missense_variant	1/9		XP_047276734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STX1A	ENST00000222812.8	c.26G>A	p.Arg9His	missense_variant	1/10	1	NM_004603.4	ENSP00000222812.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000284 AC: 3 AN: 1055004 Hom.: 0 Cov.: 30 AF XY: 0.00000201 AC XY: 1 AN XY: 497712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2023

The c.26G>A (p.R9H) alteration is located in exon 1 (coding exon 1) of the STX1A gene. This alteration results from a G to A substitution at nucleotide position 26, causing the arginine (R) at amino acid position 9 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.092
Sift	Benign	0.048	D;D;D;D
Sift4G	Benign	0.068	T;T;D;T
Polyphen		0.19	B;P;.;.
Vest4		0.15
MutPred		0.27		Gain of glycosylation at S14 (P = 0.1058);Gain of glycosylation at S14 (P = 0.1058);Gain of glycosylation at S14 (P = 0.1058);Gain of glycosylation at S14 (P = 0.1058);
MVP		0.58
MPC		1.2
ClinPred		0.87	D
GERP RS		3.1
Varity_R		0.14
gMVP		0.17

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: rs1799424088; hg19: chr7-73133936;