rs79299301
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2
The NM_016169.4(SUFU):c.1028G>A(p.Arg343His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,614,080 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. R343C) has been classified as Likely benign.
Frequency
Consequence
NM_016169.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUFU | NM_016169.4 | c.1028G>A | p.Arg343His | missense_variant | 9/12 | ENST00000369902.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUFU | ENST00000369902.8 | c.1028G>A | p.Arg343His | missense_variant | 9/12 | 1 | NM_016169.4 | P1 | |
SUFU | ENST00000423559.2 | c.1028G>A | p.Arg343His | missense_variant | 9/10 | 1 | |||
SUFU | ENST00000369899.6 | c.1028G>A | p.Arg343His | missense_variant | 9/11 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152086Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251430Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135904
GnomAD4 exome AF: 0.000171 AC: 250AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 118AN XY: 727240
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152202Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74408
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal history of chondroma (Yepes et al., 2021); This variant is associated with the following publications: (PMID: 24728327, 26336887, 34070849) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The SUFU p.R343H variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs79299301), Cosmic and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Illumina and Fulgent Genetics). The variant was identified in control databases in 23 of 282820 chromosomes at a frequency of 0.00008132 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 7224 chromosomes (freq: 0.000277), European (non-Finnish) in 19 of 129150 chromosomes (freq: 0.000147), African in 1 of 24960 chromosomes (freq: 0.00004) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.R343 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2023 | The SUFU c.1028G>A; p.Arg343His variant (rs79299301) is reported in the literature in an individual affected with chordoma, but without clear disease association (Yepes 2021). This variant is also reported in ClinVar (Variation ID: 135285), and is found in the non-Finnish European population with an allele frequency of 0.015% (19/129150 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.473). Due to limited information, the clinical significance of this variant is uncertain at this time. - |
Familial meningioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 05, 2023 | - - |
Medulloblastoma Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
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 | - - |
Gorlin syndrome;C0025149:Medulloblastoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2021 | 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. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at