rs778125780
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The NM_016169.4(SUFU):āc.1379A>Gā(p.Lys460Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. K460T) 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 -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUFU | NM_016169.4 | c.1379A>G | p.Lys460Arg | missense_variant | 12/12 | ENST00000369902.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUFU | ENST00000369902.8 | c.1379A>G | p.Lys460Arg | missense_variant | 12/12 | 1 | NM_016169.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251420Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135888
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74312
ClinVar
Submissions by phenotype
Gorlin syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 09, 2022 | The SUFU c.1379A>G (p.Lys460Arg) missense change has a maximum subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function. Transduction of a cell line with this variant led to an increase in Hedgehog pathway activity as compared to the wild-type, suggesting that this variant may have dominant-negative activity and can interfere with function of the wild-type protein (PMID: 29654263). To our knowledge, this variant has not been reported in individuals with nevoid basal cell carcinoma syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 17, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2023 | This alteration is classified as 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 27, 2022 | - - |
Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 460 of the SUFU protein (p.Lys460Arg). This variant is present in population databases (rs778125780, gnomAD 0.03%). 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: 453960). 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 not expected to disrupt SUFU protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SUFU function (PMID: 29654263). 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. - |
Familial meningioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 31, 2019 | - - |
Gorlin syndrome;C0025149:Medulloblastoma;C3551915:Familial meningioma;C4540342:Joubert syndrome 32 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at