10-102597221-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_016169.4(SUFU):c.838C>T(p.Arg280Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R280Q) has been classified as Likely benign.
Frequency
Consequence
NM_016169.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SUFU | ENST00000369902.8 | c.838C>T | p.Arg280Trp | missense_variant | Exon 7 of 12 | 1 | NM_016169.4 | ENSP00000358918.4 | ||
SUFU | ENST00000423559.2 | c.838C>T | p.Arg280Trp | missense_variant | Exon 7 of 10 | 1 | ENSP00000411597.2 | |||
SUFU | ENST00000369899.6 | c.838C>T | p.Arg280Trp | missense_variant | Exon 7 of 11 | 1 | ENSP00000358915.2 | |||
SUFU | ENST00000471000.1 | n.620C>T | non_coding_transcript_exon_variant | Exon 5 of 6 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152000Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251450Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727226
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152000Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74214
ClinVar
Submissions by phenotype
Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 280 of the SUFU protein (p.Arg280Trp). This variant is present in population databases (rs761003435, gnomAD 0.0008%). 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: 574724). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SUFU protein function with a negative predictive value of 80%. 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
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24311597) -
Familial meningioma Uncertain:1
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Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at