rs1346726468

Positions:

• chr9-127690835-C-G
• chr9-127690835-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000373299.5(STXBP1):​c.1763C>G​(p.Thr588Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. T588I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 ENST00000373299.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.37

Genes affected

STXBP1 (HGNC:11444): (syntaxin binding protein 1) This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

(HGNC:):

PTRH1 (HGNC:27039): (peptidyl-tRNA hydrolase 1 homolog) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

MIR3911 (HGNC:38962): (microRNA 3911) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STXBP1. . Gene score misZ 4.263 (greater than the threshold 3.09). Trascript score misZ 5.8379 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant non-syndromic intellectual disability, Dravet syndrome, undetermined early-onset epileptic encephalopathy, autism spectrum disorder, developmental and epileptic encephalopathy, West syndrome, atypical Rett syndrome, developmental and epileptic encephalopathy, 4.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17944133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_001032221.6	c.1763C>G	p.Thr588Arg	missense_variant	19/19	ENST00000373299.5	NP_001027392.1
STXBP1	NM_003165.6	c.*77C>G		3_prime_UTR_variant	20/20	ENST00000373302.8	NP_003156.1
MIR3911	NR_037473.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373299.5	c.1763C>G	p.Thr588Arg	missense_variant	19/19	1	NM_001032221.6	ENSP00000362396	A1
STXBP1	ENST00000373302.8	c.*77C>G		3_prime_UTR_variant	20/20	1	NM_003165.6	ENSP00000362399	P3
	ENST00000624141.1	n.6G>C		non_coding_transcript_exon_variant	1/1
MIR3911	ENST00000577791.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0036	T;T;T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.20	.;.;N
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	-0.090	.;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.44	.;.;T
Sift4G	Benign	0.34	.;.;T
Polyphen		0.17	.;.;B
Vest4		0.40
MutPred		0.24		.;.;Gain of solvent accessibility (P = 0.0456);
MVP		0.63
ClinPred		0.57	D
GERP RS		4.3
Varity_R		0.094

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

Publications

LitVar

Other links and lift over

dbSNP: rs1346726468; hg19: chr9-130453114;