chr7-73705171-T-G

Variant names:

• chr7-73705171-T-G
• NM_004603.4:c.262A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004603.4(STX1A):​c.262A>C​(p.Lys88Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STX1A NM_004603.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

LOC105375350 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.3989 (below the threshold of 3.09). Trascript score misZ: 2.9044 (below the threshold of 3.09). GenCC associations: The gene is linked to cystic fibrosis, complex neurodevelopmental disorder, neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35653725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STX1A	NM_004603.4	c.262A>C	p.Lys88Gln	missense_variant	Exon 4 of 10	ENST00000222812.8	NP_004594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STX1A	ENST00000222812.8	c.262A>C	p.Lys88Gln	missense_variant	Exon 4 of 10	1	NM_004603.4	ENSP00000222812.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.262A>C (p.K88Q) alteration is located in exon 4 (coding exon 4) of the STX1A gene. This alteration results from a A to C substitution at nucleotide position 262, causing the lysine (K) at amino acid position 88 to be replaced by a glutamine (Q). 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	Benign	0.18
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.40	T;.;T;.
Eigen	Benign	-0.040
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;.;.
PhyloP100		6.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	D;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.091	T;T;T;T
Sift4G	Benign	0.083	T;T;T;T
Polyphen		0.0010	B;B;.;.
Vest4		0.53
MutPred		0.49		Gain of ubiquitination at K84 (P = 0.0338);Gain of ubiquitination at K84 (P = 0.0338);Gain of ubiquitination at K84 (P = 0.0338);Gain of ubiquitination at K84 (P = 0.0338);
MVP		0.74
MPC		0.99
ClinPred		0.89	D
GERP RS		4.7
Varity_R		0.50
gMVP		0.51
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

hg19: chr7-73119501;