7-73702969-G-T

Variant names:

• chr7-73702969-G-T
• rs2116731315
• NM_004603.4:c.554C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_004603.4(STX1A):​c.554C>A​(p.Ser185Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S185C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STX1A NM_004603.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-73702969-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1679129.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STX1A	NM_004603.4	c.554C>A	p.Ser185Tyr	missense_variant	Exon 8 of 10	ENST00000222812.8	NP_004594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STX1A	ENST00000222812.8	c.554C>A	p.Ser185Tyr	missense_variant	Exon 8 of 10	1	NM_004603.4	ENSP00000222812.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455332 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723846

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109060

Other (OTH) AF: 0.00 AC: 0 AN: 60128

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	M;M;.;.
PhyloP100		9.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.64	P;D;.;.
Vest4		0.79
MutPred		0.42		Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);
MVP		0.65
MPC		2.2
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.87
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2116731315; hg19: chr7-73117299;