rs12573787
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BA1
The NM_000314.8(PTEN):c.-511G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 381,510 control chromosomes in the GnomAD database, including 4,826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.13 ( 1493 hom., cov: 31)
Exomes 𝑓: 0.15 ( 3333 hom. )
Consequence
PTEN
NM_000314.8 5_prime_UTR
NM_000314.8 5_prime_UTR
Scores
1
1
Clinical Significance
Conservation
PhyloP100: 2.14
Genes affected
PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 10-87863959-G-A is Benign according to our data. Variant chr10-87863959-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 810888.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_pathogenic=1}. Variant chr10-87863959-G-A is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.-511G>A | 5_prime_UTR_variant | 1/9 | ENST00000371953.8 | ||
PTEN | NM_001304717.5 | c.10G>A | p.Gly4Arg | missense_variant | 1/10 | ||
PTEN | NM_001304718.2 | c.-1215G>A | 5_prime_UTR_variant | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.-511G>A | 5_prime_UTR_variant | 1/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.126 AC: 18970AN: 150292Hom.: 1491 Cov.: 31
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GnomAD4 exome AF: 0.154 AC: 35529AN: 231108Hom.: 3333 Cov.: 0 AF XY: 0.152 AC XY: 18136AN XY: 119532
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GnomAD4 genome ? AF: 0.126 AC: 18981AN: 150402Hom.: 1493 Cov.: 31 AF XY: 0.127 AC XY: 9318AN XY: 73528
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Jan 24, 2024 | This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 36. Only high quality variants are reported. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Myeloproliferative neoplasm, unclassifiable Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology | Aug 25, 2022 | - - |
PTEN-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 19, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
PTEN hamartoma tumor syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
Cadd
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Dann
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RBP_binding_hub_radar
RBP_regulation_power_radar
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