chr7-73700781-C-T

Variant names:

• chr7-73700781-C-T
• rs369491721
• ENST00000395156.7:c.692G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_001165903.2(STX1A):​c.692G>A​(p.Gly231Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: STX1A NM_001165903.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.114
• 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):

• neurodevelopmental disorder

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, G2P
• complex neurodevelopmental disorder

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 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: 2.6361 (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=0.0725722).
• BP6: Variant 7-73700781-C-T is Benign according to our data. Variant chr7-73700781-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3802740.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165903.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX1A	NM_004603.4	MANE Select	c.738G>A	p.Arg246Arg	synonymous	Exon 9 of 10	NP_004594.1	Q75ME0
	STX1A	NM_001165903.2		c.692G>A	p.Gly231Glu	missense	Exon 9 of 10	NP_001159375.1	Q16623-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX1A	ENST00000395156.7	TSL:1	c.692G>A	p.Gly231Glu	missense	Exon 9 of 10	ENSP00000378585.3	Q16623-3
	STX1A	ENST00000222812.8	TSL:1 MANE Select	c.738G>A	p.Arg246Arg	synonymous	Exon 9 of 10	ENSP00000222812.3	Q16623-1
	STX1A	ENST00000929307.1		c.852G>A	p.Arg284Arg	synonymous	Exon 10 of 11	ENSP00000599366.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251390 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.4
DANN	Uncertain	0.98
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.11
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.063
Sift	Benign	0.25	T
Sift4G	Benign	0.095	T
Polyphen		0.0	B
Vest4		0.27
MVP		0.40
ClinPred		0.087	T
GERP RS		-0.75
Mutation Taster		=84/16	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

dbSNP: rs369491721; hg19: chr7-73115111;