rs431905512
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003764.4(STX11):c.173T>C(p.Leu58Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L58L) has been classified as Likely benign.
Frequency
Consequence
NM_003764.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STX11 | NM_003764.4 | c.173T>C | p.Leu58Pro | missense_variant | 2/2 | ENST00000367568.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STX11 | ENST00000367568.5 | c.173T>C | p.Leu58Pro | missense_variant | 2/2 | 1 | NM_003764.4 | P1 | |
STX11 | ENST00000698355.1 | c.173T>C | p.Leu58Pro | missense_variant | 3/3 | P1 | |||
STX11 | ENST00000698356.1 | c.173T>C | p.Leu58Pro | missense_variant | 4/4 | P1 | |||
STX11 | ENST00000698357.1 | c.173T>C | p.Leu58Pro | missense_variant | 2/2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250684Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135742
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461524Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727084
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 4 Pathogenic:3Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 14, 2014 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 58 of the STX11 protein (p.Leu58Pro). This variant is present in population databases (rs431905512, gnomAD 0.007%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 24459464, 26004995; Invitae). ClinVar contains an entry for this variant (Variation ID: 97001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STX11 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STX11 function (PMID: 24459464). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Apr 25, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at