rs786204887
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001126049.2(KLLN):c.-914_-889del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000792 in 340,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000079 ( 0 hom. )
Consequence
KLLN
NM_001126049.2 5_prime_UTR
NM_001126049.2 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.12
Genes affected
KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]
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 Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAd4 at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLLN | NM_001126049.2 | c.-914_-889del | 5_prime_UTR_variant | 1/1 | ENST00000445946.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLLN | ENST00000445946.5 | c.-914_-889del | 5_prime_UTR_variant | 1/1 | NM_001126049.2 | P1 | |||
PTEN | ENST00000688308.1 | c.-17+269_-17+294del | intron_variant | P1 | |||||
PTEN | ENST00000693560.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000790 AC: 12AN: 151974Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000794 AC: 15AN: 188882Hom.: 0 AF XY: 0.0000734 AC XY: 7AN XY: 95430
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 19, 2021 | To the best of our knowledge, the variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2021 | Describes a deletion of 26 nucleotides from 1063 to 1088 basepairs upstream of the ATG translational start site in the PTEN promoter region; Has not been previously published as pathogenic or benign to our knowledge; Variants within the PTEN promoter have been observed in individuals with features of Cowden syndrome (Zhou 2003); Also known as -1087_-1062del26; This variant is associated with the following publications: (PMID: 12844284) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2017 | Variant summary: The PTEN variant c.-1087_1062del26 (alternatively also known as c.-1088_1063del26) is located within the promoter region of the gene (between -1344 bp and -745 bp upstream from initiation codon). Mutation taster predicts damaging outcome for this variant. This nucleotide position has no coverage in ExAC, NHLBI ESP and 1000 Genomes, however has been covered in gnomAD (1/30820 control chromosomes). The variant of interest has not, to our knowledge, been reported in literature/databases, nor evaluated for functional impact by in vivo/vitro studies. Two clinical laboratories in ClinVar have classified it as variant of uncertain significance. Several single nucleotide substitutions and deletion/duplication variants in promoter region are reported in patients with Cowden syndrome and known to decrease PTEN transcription (refs. ClinVar, HGMD, Zhou_2003, among others). Therefore this variant may also have similar outcome. Taken together, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
PTEN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 06, 2023 | The PTEN c.-1088_-1063del26 variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2020 | 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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Find out detailed SpliceAI scores and Pangolin per-transcript scores at