rs201326378
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP3_ModerateBS1_SupportingBS2
The NM_016169.4(SUFU):c.1177C>T(p.Arg393Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,614,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. R393Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_016169.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUFU | NM_016169.4 | c.1177C>T | p.Arg393Trp | missense_variant | 10/12 | ENST00000369902.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUFU | ENST00000369902.8 | c.1177C>T | p.Arg393Trp | missense_variant | 10/12 | 1 | NM_016169.4 | P1 | |
SUFU | ENST00000423559.2 | c.1177C>T | p.Arg393Trp | missense_variant | 10/10 | 1 | |||
SUFU | ENST00000369899.6 | c.1177C>T | p.Arg393Trp | missense_variant | 10/11 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251492Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461892Hom.: 1 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727246
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152336Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74488
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 30, 2021 | DNA sequence analysis of the SUFU gene demonstrated a sequence change, c.1177C>T, in exon 10 that results in an amino acid change, p.Arg393Trp. This sequence change has been described in gnomAD with a frequency of 0.005% in the South Asian sub-population (dbSNP rs201326378). The p.Arg393Trp change affects a highly conserved amino acid residue located in a domain of the SUFU protein that is known to be functional. The p.Arg393Trp substitution appears to damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with SUFU-related disorders and has also not been described as a known benign sequence change in the SUFU gene. Due to the lack sufficient evidences, the clinical significance of the p.Arg393Trp change remains unknown at this time. - |
Gorlin syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 24, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 393 of the SUFU protein (p.Arg393Trp). This variant is present in population databases (rs201326378, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SUFU-related conditions. ClinVar contains an entry for this variant (Variation ID: 524656). 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 SUFU protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. - |
Familial meningioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 18, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2023 | The p.R393W variant (also known as c.1177C>T), located in coding exon 10 of the SUFU gene, results from a C to T substitution at nucleotide position 1177. The arginine at codon 393 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at