rs1554897280

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong

The NM_000314.8(PTEN):c.209+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTEN
NM_000314.8 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.29

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018151816 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of 4, new splice context is: taaGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 10-87925558-G-A is Pathogenic according to our data. Variant chr10-87925558-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 418434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
PTEN	NM_000314.8 linkuse as main transcript	c.209+1G>A	splice_donor_variant	ENST00000371953.8
PTEN	NM_001304717.5 linkuse as main transcript	c.728+1G>A	splice_donor_variant
PTEN	NM_001304718.2 linkuse as main transcript	c.-540-5488G>A	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.209+1G>A		splice_donor_variant		1	NM_000314.8	P1	P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1414990

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705560

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2023

This sequence change affects a donor splice site in intron 3 of the PTEN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 16014636). ClinVar contains an entry for this variant (Variation ID: 418434). This variant is also known as IVS3+1G>A. Disruption of this splice site has been observed in individuals with clinical features of PTEN-related conditions (PMID: 10234502, 10400993, 17526801, 21194675, 21659347, 23335809). This variant is not present in population databases (gnomAD no frequency). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2021

Canonical splice site variant demonstrated to result in exon 3 skipping, resulting in an in-frame deletion disrupting the critical phosphatase domain and an ATP binding region (Agrawal 2005, Lobo 2009, Molinari 2014); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 11071384, 15372512, 12938083, 14518068, 17526801, 10400993, 16014636, 24475377, 19457929, 26582918, 28677221) -

Familial meningioma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 30, 2018

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5. -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 01, 2022

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.209+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the PTEN gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Functional analysis using patient mRNA has shown that this transcript has significantly reduced protein phosphatase activity despite being in-frame and stable due to exon 3 skipping (Agrawal S et al. Hum Mol Genet, 2005 Aug;14:2459-68). Moreover, this alteration has been reported in a individual with presumed sporadic Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Marsh DJ et al. Hum. Mol. Genet., 1999 Aug;8:1461-72) and in cohorts of patients with features of Cowden syndrome (CS) and/or BRRS (Pilarski R et al. J Med Genet, 2011 Aug;48:505-12; Tan MH et al. Am J Hum Genet. 2011 Jan;88(1):42-56). Specifically, this mutation was identified in an 11-year-old female with macrocephaly, vascular anomalies, lipoma, and Graves disease (Tan WH et al. J Med Genet, 2007 Sep;44:594-602). Another alteration impacting the same donor site (c.209+4A>G) has been shown to have a similar impact on splicing in an individual diagnosed with breast and endometrial cancer at less than 50 years of age (Ambry internal data). Of note, this alteration is also designated as IVS3+1G>A in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

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