GeneBe

rs786203676

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000693560.1(PTEN):​c.-402G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PTEN
ENST00000693560.1 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.61

Publications

0 publications found
Variant links:
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]
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]
KLLN Gene-Disease associations (from GenCC):
  • Cowden disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Cowden syndrome 4
    Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTENNM_000314.8 linkc.-922G>A upstream_gene_variant ENST00000371953.8 NP_000305.3
KLLNNM_001126049.2 linkc.-1061C>T upstream_gene_variant ENST00000445946.5 NP_001119521.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTENENST00000371953.8 linkc.-922G>A upstream_gene_variant 1 NM_000314.8 ENSP00000361021.3
KLLNENST00000445946.5 linkc.-1061C>T upstream_gene_variant 6 NM_001126049.2 ENSP00000392204.2
MLDHRENST00000692337.1 linkc.-11G>A upstream_gene_variant ENSP00000509326.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
233608
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
118748
African (AFR)
AF:
0.00
AC:
0
AN:
6590
American (AMR)
AF:
0.00
AC:
0
AN:
6934
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
8582
East Asian (EAS)
AF:
0.00
AC:
0
AN:
22196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2656
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
20596
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1232
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
149466
Other (OTH)
AF:
0.00
AC:
0
AN:
15356
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
-
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Uncertain:1
Feb 26, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1
Jun 21, 2018
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.-921G>A variant is located in the 5' untranslated region (5’ UTR) of the PTEN gene. This variant results from a G to A substitution 921 bases upstream from the first translated codon. Another alteration at the same position (designated as c.-920G>T) has been reported in an individual with PTEN hamartoma tumor syndrome (Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73:404-11). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
18
DANN
Benign
0.96
PhyloP100
2.6
PromoterAI
-0.095
Neutral

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs786203676; hg19: chr10-89623305; API