11-59773216-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004177.5(STX3):c.36G>C(p.Gln12His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q12E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: STX3 NM_004177.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

Genes affected

STX3 (HGNC:11438): (syntaxin 3) The gene is a member of the syntaxin family. The encoded protein is targeted to the apical membrane of epithelial cells where it forms clusters and is important in establishing and maintaining polarity necessary for protein trafficking involving vesicle fusion and exocytosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22482717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STX3	NM_004177.5	c.36G>C	p.Gln12His	missense_variant	2/11	ENST00000337979.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STX3	ENST00000337979.9	c.36G>C	p.Gln12His	missense_variant	2/11	1	NM_004177.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251274 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461774 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2022

This variant is present in population databases (rs755445972, gnomAD 0.003%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with STX3-related conditions. This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 12 of the STX3 protein (p.Gln12His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.073	T;.;.
Eigen	Benign	0.014
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.5	N;.;N
REVEL	Benign	0.050
Sift	Uncertain	0.012	D;.;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.70	P;.;.
Vest4		0.39
MutPred		0.25		Loss of ubiquitination at K9 (P = 0.1904);Loss of ubiquitination at K9 (P = 0.1904);Loss of ubiquitination at K9 (P = 0.1904);
MVP		0.70
MPC		0.23
ClinPred		0.44	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs755445972; hg19: chr11-59540689;