rs149449923
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_016169.4(SUFU):c.1105G>A(p.Val369Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_016169.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SUFU | ENST00000369902.8 | c.1105G>A | p.Val369Ile | missense_variant | Exon 9 of 12 | 1 | NM_016169.4 | ENSP00000358918.4 | ||
SUFU | ENST00000423559.2 | c.1105G>A | p.Val369Ile | missense_variant | Exon 9 of 10 | 1 | ENSP00000411597.2 | |||
SUFU | ENST00000369899.6 | c.1105G>A | p.Val369Ile | missense_variant | Exon 9 of 11 | 1 | ENSP00000358915.2 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152094Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251480Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135918
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727240
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6AN XY: 74420
ClinVar
Submissions by phenotype
not provided Uncertain:2
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In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 32278351, 30256826) -
not specified Uncertain:1Other:1
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The SUFU c.1105G>A; p.Val369Ile variant (rs149449923), to our knowledge, is not reported in the medical literature but is reported as having uncertain significance in ClinVar (Variation ID: 135286). This variant is found in the East Asian population with an allele frequency of 0.06% (11/18870 alleles) in the Genome Aggregation Database. The valine at codon 369 is highly conserved but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Val369Ile variant is uncertain at this time. -
Medulloblastoma;C3551915:Familial meningioma;C4540342:Joubert syndrome 32;C5830451:Basal cell nevus syndrome 2 Uncertain:1
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Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 369 of the SUFU protein (p.Val369Ile). This variant is present in population databases (rs149449923, gnomAD 0.06%). 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: 135286). 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. -
Familial meningioma Uncertain:1
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Hereditary cancer-predisposing syndrome Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at