chr7-73708593-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004603.4(STX1A):​c.204T>A​(p.Asp68Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: STX1A NM_004603.4 missense
• 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: Uncertain_significance. 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: 2.9044 (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=0.086076885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STX1A	NM_004603.4	c.204T>A	p.Asp68Glu	missense_variant	Exon 3 of 10	ENST00000222812.8	NP_004594.1
STX1A	NM_001165903.2	c.204T>A	p.Asp68Glu	missense_variant	Exon 3 of 10		NP_001159375.1
STX1A	XM_047420777.1	c.204T>A	p.Asp68Glu	missense_variant	Exon 3 of 9		XP_047276733.1
STX1A	XM_047420778.1	c.204T>A	p.Asp68Glu	missense_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>A	p.Asp68Glu	missense_variant	Exon 3 of 10	1	NM_004603.4	ENSP00000222812.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460730 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 726602

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111406

Other (OTH) AF: 0.00 AC: 0 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.1
DANN	Benign	0.90
DEOGEN2	Benign	0.38	T;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.086	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L;L;.;.
PhyloP100		-3.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.74	T;T;T;T
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.22
MutPred		0.45		Gain of glycosylation at P65 (P = 0.1253);Gain of glycosylation at P65 (P = 0.1253);Gain of glycosylation at P65 (P = 0.1253);Gain of glycosylation at P65 (P = 0.1253);
MVP		0.62
MPC		1.3
ClinPred		0.091	T
GERP RS		-6.4
Varity_R		0.072
gMVP		0.39
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;