10-87960876-CTTTTTTTTT-CTTTTTTTTTT

Position:

• chr10-87960876-CTTTTTTTTT-CTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_000314.8(PTEN):​c.802-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,355,092 control chromosomes in the GnomAD database, including 1,748 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1553 hom., cov: 26)
  • Exomes 𝑓: 0.20 (195 hom.)
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.37

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.18481848 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: tcttttttttttttttttAGgac. 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-CT is Benign according to our data. Variant chr10-87960876-C-CT is described in ClinVar as [Benign]. Clinvar id is 92831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.802-3dupT		splice_acceptor_variant, intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1321-3dupT		splice_acceptor_variant, intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.211-3dupT		splice_acceptor_variant, intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.802-3dupT		splice_acceptor_variant, intron_variant		1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.160 AC: 20003 AN: 125032 Hom.: 1554 Cov.: 26

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0651

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.171

GnomAD4 exome AF: 0.196 AC: 241101 AN: 1230064 Hom.: 195 Cov.: 0 AF XY: 0.193 AC XY: 118293 AN XY: 612234

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.290

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.160 AC: 20003 AN: 125028 Hom.: 1553 Cov.: 26 AF XY: 0.160 AC XY: 9650 AN XY: 60366

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.362

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.171

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

PTEN hamartoma tumor syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Sep 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs34003473; hg19: chr10-89720633;