rs886047384

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_ModerateBP6_Very_Strong

The NM_000314.8(PTEN):c.-735G>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 0.0000181 in 387,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PTEN
NM_000314.8 5_prime_UTR

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:2

Conservation

PhyloP100: 0.933

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]

PTEN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 10-87863735-G-A is Benign according to our data. Variant chr10-87863735-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127672.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
PTEN	NM_000314.8 linkuse as main transcript	c.-735G>A	5_prime_UTR_variant	1/9	ENST00000371953.8
PTEN	NM_001304717.5 linkuse as main transcript	c.-215G>A	5_prime_UTR_variant	1/10
PTEN	NM_001304718.2 linkuse as main transcript	c.-1439G>A	5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.-735G>A		5_prime_UTR_variant	1/9	1	NM_000314.8	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.0000203

AC:

AN:

147774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000646

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000167

AC:

AN:

239478

Hom.:

Cov.:

AF XY:

0.0000164

AC XY:

AN XY:

121742

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00100

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000633

GnomAD4 genome

AF:

0.0000203

AC:

AN:

147774

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

72212

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000646

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2015	This variant is denoted PTEN c.-735G>A, and describes a nucleotide substitution 735 base pairs upstream of the ATG translational start site in the PTEN promoter region. The surrounding sequence, with the base that is substituted in brackets, is GCCC[G/A]GAGC. This variant, also called c.-734G>A using alternate numbering, has not been published in the literature to our knowledge. One study found that approximately 9% (9/95) of patients with Cowden syndrome (CS) were identified to have a point variant in the PTEN core promoter region (c.-798 to c.-1238) (Zhou 2003). While the c.-735G>A variant is outside of this core promoter region, it could still have an effect on transcription and, possibly, PTEN protein levels. Based on the currently available information, we consider this to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2016	- -

PTEN hamartoma tumor syndrome

Uncertain:1Benign:1

Likely benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Aug 04, 2023	NM_000314.8(PTEN):c.-735G>A meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF in gnomAD for South Asians: 0.01758%. Per ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3, 1 Benign Strong = Likely Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 21, 2020

- -

Cowden syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Feb 06, 2018

Research exome identified causative de novo mutation in PPP2R5D that explains proband's phenotype reducing the likelihood the PTEN c.-734G>A is associated with disease. The mother of the observed proband also carries variant and does not have features of PHTS/Cowden's syndrome. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

Cadd

Benign

Dann

Uncertain

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over