NM_000314.8:c.49C>T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000314.8(PTEN):c.49C>T(p.Gln17*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q17Q) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PTEN
NM_000314.8 stop_gained
NM_000314.8 stop_gained
Scores
4
2
Clinical Significance
Conservation
PhyloP100: 7.07
Publications
14 publications found
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]
PTEN Gene-Disease associations (from GenCC):
- Cowden syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
- PTEN hamartoma tumor syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- macrocephaly-autism syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
- renal cell carcinomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- leiomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- activated PI3K-delta syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Bannayan-Riley-Ruvalcaba syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Cowden diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Lhermitte-Duclos diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Proteus-like syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- glioma susceptibility 2Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1086 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-87864518-C-T is Pathogenic according to our data. Variant chr10-87864518-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 189458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | MANE Select | c.49C>T | p.Gln17* | stop_gained | Exon 1 of 9 | NP_000305.3 | ||
| PTEN | NM_001304717.5 | c.568C>T | p.Gln190* | stop_gained | Exon 2 of 10 | NP_001291646.4 | |||
| PTEN | NM_001304718.2 | c.-657C>T | 5_prime_UTR | Exon 1 of 9 | NP_001291647.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PTEN | ENST00000371953.8 | TSL:1 MANE Select | c.49C>T | p.Gln17* | stop_gained | Exon 1 of 9 | ENSP00000361021.3 | ||
| PTEN | ENST00000693560.1 | c.568C>T | p.Gln190* | stop_gained | Exon 2 of 10 | ENSP00000509861.1 | |||
| PTEN | ENST00000700029.2 | c.49C>T | p.Gln17* | stop_gained | Exon 1 of 10 | ENSP00000514759.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461844Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727228
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461844
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
727228
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
0
AN:
86244
European-Finnish (FIN)
AF:
AC:
0
AN:
53412
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111994
Other (OTH)
AF:
AC:
0
AN:
60394
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts