rs876659695
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 6P and 8B. PVS1_ModeratePM2PP3_ModerateBP6_Very_Strong
The NM_000314.8(PTEN):c.253+4_253+7del variant causes a splice donor, coding sequence change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,452,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Consequence
NM_000314.8 splice_donor, coding_sequence
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.253+4_253+7del | splice_donor_variant, coding_sequence_variant | 4/9 | ENST00000371953.8 | ||
PTEN | NM_001304717.5 | c.772+4_772+7del | splice_donor_variant, coding_sequence_variant | 5/10 | |||
PTEN | NM_001304718.2 | c.-497+3_-497+6del | splice_donor_variant, 5_prime_UTR_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.253+4_253+7del | splice_donor_variant, coding_sequence_variant | 4/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1452808Hom.: 0 AF XY: 0.00000277 AC XY: 2AN XY: 723096
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 04, 2020 | This variant results in a 4 nucleotide deletion in the splice donor region in intron 4 of the PTEN gene. To our knowledge, RNA functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2018 | 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 10, 2022 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2018 | This variant is denoted PTEN c.253+4_253+7delGGTA or IVS4+4_IVS4+7delGGTA and consists of a deletion of four nucleotides at the +4 to +7 position in intron 4 of the PTEN gene. The normal sequence with the bases that are deleted in brackets is Ggta[delggta]tgaa, where the capital letter is exonic and lowercase letters are intronic. This variant is not predicted to cause abnormal splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. PTEN c.253+4_253+7delGGTA was not observed in large population cohorts (Lek 2016). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Two of the nucleotides that are deleted are conserved across species. Based on currently available evidence, it is unclear whether PTEN c.253+4_253+7delGGTA is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 30, 2017 | - - |
PTEN hamartoma tumor syndrome Benign:2
Likely benign, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Jun 18, 2020 | PTEN c.253+4_253+7delGGTA meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (internal laboratory contributor(s) SCV000276425.5) BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact. PM2: Absent in large sequenced populations (PMID 27535533) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at