rs189234140
Positions:
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_016169.4(SUFU):c.12G>A(p.Leu4=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000737 in 1,544,724 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0039 ( 6 hom., cov: 33)
Exomes 𝑓: 0.00040 ( 0 hom. )
Consequence
SUFU
NM_016169.4 synonymous
NM_016169.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 5.52
Genes affected
SUFU (HGNC:16466): (SUFU negative regulator of hedgehog signaling) The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -18 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 10-102504164-G-A is Benign according to our data. Variant chr10-102504164-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102504164-G-A is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00386 (587/152208) while in subpopulation AFR AF= 0.0135 (560/41538). AF 95% confidence interval is 0.0126. There are 6 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 587 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUFU | NM_016169.4 | c.12G>A | p.Leu4= | synonymous_variant | 1/12 | ENST00000369902.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUFU | ENST00000369902.8 | c.12G>A | p.Leu4= | synonymous_variant | 1/12 | 1 | NM_016169.4 | P1 | |
SUFU | ENST00000423559.2 | c.12G>A | p.Leu4= | synonymous_variant | 1/10 | 1 | |||
SUFU | ENST00000369899.6 | c.12G>A | p.Leu4= | synonymous_variant | 1/11 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00383 AC: 582AN: 152100Hom.: 5 Cov.: 33
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GnomAD3 exomes AF: 0.000905 AC: 132AN: 145936Hom.: 0 AF XY: 0.000743 AC XY: 59AN XY: 79380
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GnomAD4 exome AF: 0.000396 AC: 552AN: 1392516Hom.: 0 Cov.: 31 AF XY: 0.000361 AC XY: 248AN XY: 686926
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GnomAD4 genome ? AF: 0.00386 AC: 587AN: 152208Hom.: 6 Cov.: 33 AF XY: 0.00336 AC XY: 250AN XY: 74406
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 19, 2018 | Variant summary: SUFU c.12G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 171858 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 1460-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in SUFU causing Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) phenotype (1e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.12G>A in individuals affected with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 04, 2021 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SUFU: BP4, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2021 | - - |
Gorlin syndrome;C0025149:Medulloblastoma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Medulloblastoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2017 | 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
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at