NM_000314.8:c.802-7_802-3dupTTTTT

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PVS1_StrongBP6_Moderate

The NM_000314.8(PTEN):c.802-7_802-3dupTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTEN
NM_000314.8 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.37

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]

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: Uncertain_significance. The variant received 2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.18564357 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 10-87960876-C-CTTTTT is Benign according to our data. Variant chr10-87960876-C-CTTTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3903794.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.802-7_802-3dupTTTTT	splice_acceptor_variant, intron_variant	Intron 7 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.1321-7_1321-3dupTTTTT	splice_acceptor_variant, intron_variant	Intron 8 of 9		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.211-7_211-3dupTTTTT	splice_acceptor_variant, intron_variant	Intron 7 of 8		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.802-18_802-17insTTTTT		intron_variant	Intron 7 of 8	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

125128

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1300124

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

647350

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000341

AC:

AN:

26376

American (AMR)

AF:

0.0000306

AC:

AN:

32668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23502

East Asian (EAS)

AF:

0.00

AC:

AN:

35696

South Asian (SAS)

AF:

0.0000140

AC:

AN:

71372

European-Finnish (FIN)

AF:

0.0000214

AC:

AN:

46632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4954

European-Non Finnish (NFE)

AF:

0.00000597

AC:

AN:

1005266

Other (OTH)

AF:

0.0000186

AC:

AN:

53658

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000305594), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.386

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

125128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

60404

African (AFR)

AF:

0.00

AC:

AN:

31732

American (AMR)

AF:

0.00

AC:

AN:

12970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3076

East Asian (EAS)

AF:

0.00

AC:

AN:

4698

South Asian (SAS)

AF:

0.00

AC:

AN:

4066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

248

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58870

Other (OTH)

AF:

0.00

AC:

AN:

1720

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cowden syndrome 1

Benign:1

Feb 13, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Splicing

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over