7-73708593-A-G

Variant names:

• chr7-73708593-A-G
• rs2228607
• NM_004603.4:c.204T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004603.4(STX1A):​c.204T>C​(p.Asp68Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,612,352 control chromosomes in the GnomAD database, including 239,418 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.53 (21310 hom., cov: 33)
  • Exomes 𝑓: 0.54 (218108 hom.)
• Consequence: STX1A NM_004603.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.16
• Publications: 25 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-3.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STX1A	NM_004603.4	c.204T>C	p.Asp68Asp	synonymous_variant	Exon 3 of 10	ENST00000222812.8	NP_004594.1
STX1A	NM_001165903.2	c.204T>C	p.Asp68Asp	synonymous_variant	Exon 3 of 10		NP_001159375.1
STX1A	XM_047420777.1	c.204T>C	p.Asp68Asp	synonymous_variant	Exon 3 of 9		XP_047276733.1
STX1A	XM_047420778.1	c.204T>C	p.Asp68Asp	synonymous_variant	Exon 3 of 9		XP_047276734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STX1A	ENST00000222812.8	c.204T>C	p.Asp68Asp	synonymous_variant	Exon 3 of 10	1	NM_004603.4	ENSP00000222812.3

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80031 AN: 152004 Hom.: 21294 Cov.: 33

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.543

GnomAD2 exomes AF: 0.515 AC: 127851 AN: 248296 AF XY: 0.517

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.425

Gnomad ASJ exome AF: 0.631

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.523

Gnomad NFE exome AF: 0.565

Gnomad OTH exome AF: 0.550

GnomAD4 exome AF: 0.544 AC: 794674 AN: 1460230 Hom.: 218108 Cov.: 43 AF XY: 0.542 AC XY: 393799 AN XY: 726334

African (AFR) AF: 0.507 AC: 16954 AN: 33454

American (AMR) AF: 0.437 AC: 19434 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 16365 AN: 26104

East Asian (EAS) AF: 0.410 AC: 16270 AN: 39648

South Asian (SAS) AF: 0.442 AC: 38082 AN: 86096

European-Finnish (FIN) AF: 0.524 AC: 27886 AN: 53256

Middle Eastern (MID) AF: 0.699 AC: 4028 AN: 5764

European-Non Finnish (NFE) AF: 0.560 AC: 622420 AN: 1111056

Other (OTH) AF: 0.551 AC: 33235 AN: 60334

GnomAD4 genome AF: 0.526 AC: 80089 AN: 152122 Hom.: 21310 Cov.: 33 AF XY: 0.523 AC XY: 38864 AN XY: 74354

African (AFR) AF: 0.501 AC: 20790 AN: 41506

American (AMR) AF: 0.476 AC: 7284 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2200 AN: 3470

East Asian (EAS) AF: 0.431 AC: 2219 AN: 5152

South Asian (SAS) AF: 0.423 AC: 2045 AN: 4832

European-Finnish (FIN) AF: 0.520 AC: 5490 AN: 10564

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.562 AC: 38196 AN: 67990

Other (OTH) AF: 0.544 AC: 1147 AN: 2110

Alfa AF: 0.555 Hom.: 13729

Bravo AF: 0.525

Asia WGS AF: 0.411 AC: 1431 AN: 3478

EpiCase AF: 0.575

EpiControl AF: 0.567

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.37
DANN	Benign	0.61
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2228607; hg19: chr7-73122923; COSMIC: COSV56109559; COSMIC: COSV56109559;