NM_000314.8:c.*2185C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000314.8(PTEN):c.*2185C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 219,966 control chromosomes in the GnomAD database, including 589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.068 ( 419 hom., cov: 31)

Exomes 𝑓: 0.071 ( 170 hom. )

Consequence

PTEN
NM_000314.8 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.281

Publications

30 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]

PTEN Gene-Disease associations (from GenCC):

Cowden syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
PTEN hamartoma tumor syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
macrocephaly-autism syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
leiomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
activated PI3K-delta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bannayan-Riley-Ruvalcaba syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lhermitte-Duclos disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Proteus-like syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
glioma susceptibility 2
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PTEN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 10-87967657-C-T is Benign according to our data. Variant chr10-87967657-C-T is described in ClinVar as Benign. ClinVar VariationId is 301483.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.*2185C>T	3_prime_UTR_variant	Exon 9 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.*2185C>T	3_prime_UTR_variant	Exon 10 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.*2185C>T	3_prime_UTR_variant	Exon 9 of 9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.*2185C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.0681

AC:

10326

AN:

151706

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0430

Gnomad AMI

AF:

0.0749

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.0594

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.0464

Gnomad FIN

AF:

0.0737

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0657

Gnomad OTH

AF:

0.0733

GnomAD4 exome

AF:

0.0707

AC:

4820

AN:

68142

Hom.:

170

Cov.:

AF XY:

0.0718

AC XY:

2268

AN XY:

31572

show subpopulations

African (AFR)

AF:

0.0469

AC:

150

AN:

3198

American (AMR)

AF:

0.151

AC:

315

AN:

2088

Ashkenazi Jewish (ASJ)

AF:

0.0602

AC:

256

AN:

4250

East Asian (EAS)

AF:

0.0859

AC:

844

AN:

9820

South Asian (SAS)

AF:

0.0478

AC:

AN:

586

European-Finnish (FIN)

AF:

0.0945

AC:

AN:

476

Middle Eastern (MID)

AF:

0.0842

AC:

AN:

404

European-Non Finnish (NFE)

AF:

0.0659

AC:

2747

AN:

41662

Other (OTH)

AF:

0.0709

AC:

401

AN:

5658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

234

468

701

935

1169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0680

AC:

10330

AN:

151824

Hom.:

419

Cov.:

AF XY:

0.0687

AC XY:

5097

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.0428

AC:

1775

AN:

41438

American (AMR)

AF:

0.133

AC:

2024

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.0594

AC:

206

AN:

3468

East Asian (EAS)

AF:

0.121

AC:

628

AN:

5180

South Asian (SAS)

AF:

0.0462

AC:

223

AN:

4828

European-Finnish (FIN)

AF:

0.0737

AC:

774

AN:

10508

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0657

AC:

4459

AN:

67868

Other (OTH)

AF:

0.0726

AC:

153

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

463

927

1390

1854

2317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0687

Hom.:

780

Bravo

AF:

0.0734

Asia WGS

AF:

0.0690

AC:

239

AN:

3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.3

(source)

DANN

Benign

0.84

PhyloP100

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over