rs370918174

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS3BA1

This summary comes from the ClinGen Evidence Repository: PTEN c.210-39A>G (IVS3-39A>G) meets criteria to be classified as 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).BA1: Allele frequency of 0.01015 (1.01%, 252/24,818 alleles) in the European (Finnish) subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) LINK:https://erepo.genome.network/evrepo/ui/classification/CA059509/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 12 hom. )

Consequence

PTEN
NM_000314.8 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: 1.20

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:

PTEN (HGNC:):

PTEN links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
PTEN	NM_000314.8 linkuse as main transcript	c.210-39A>G	intron_variant	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.729-39A>G	intron_variant		NP_001291646.4	P60484
PTEN	NM_001304718.2 linkuse as main transcript	c.-541-39A>G	intron_variant		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.210-39A>G		intron_variant		1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

274

AN:

151760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000921

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00998

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00251

AC:

614

AN:

244962

Hom.:

AF XY:

0.00287

AC XY:

381

AN XY:

132536

show subpopulations

Gnomad AFR exome

AF:

0.000316

Gnomad AMR exome

AF:

0.000441

Gnomad ASJ exome

AF:

0.00222

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00503

Gnomad FIN exome

AF:

0.00983

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.00235

GnomAD4 exome

AF:

0.00191

AC:

2651

AN:

1389108

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

1432

AN XY:

694514

show subpopulations

Gnomad4 AFR exome

AF:

0.000220

Gnomad4 AMR exome

AF:

0.000656

Gnomad4 ASJ exome

AF:

0.00259

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00486

Gnomad4 FIN exome

AF:

0.0106

Gnomad4 NFE exome

AF:

0.00140

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00180

AC:

274

AN:

151878

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

159

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000920

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00998

Gnomad4 NFE

AF:

0.00182

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00215

Hom.:

Bravo

AF:

0.000956

Asia WGS

AF:

0.000870

AC:

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 21, 2022	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cowden syndrome 1

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

May 26, 2017

- -

PTEN hamartoma tumor syndrome

Benign:1

Benign, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Jun 18, 2020

PTEN c.210-39A>G (IVS3-39A>G) meets criteria to be classified as 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). BA1: Allele frequency of 0.01015 (1.01%, 252/24,818 alleles) in the European (Finnish) subpopulation of the gnomAD cohort. (PMID 27535533) BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 28677221) -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 20, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.7

DANN

Benign

0.67

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