10-87960876-CT-C

Position:

• chr10-87960876-CT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000314.8(PTEN):​c.802-3del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 124,968 control chromosomes in the GnomAD database, including 38 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (38 hom., cov: 26)
  • Exomes 𝑓: 0.20 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• 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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 10-87960876-CT-C is Benign according to our data. Variant chr10-87960876-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 229653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87960876-CT-C is described in Lovd as [Benign]. Variant chr10-87960876-CT-C is described in Lovd as [Benign]. Variant chr10-87960876-CT-C is described in Lovd as [Likely_benign]. Variant chr10-87960876-CT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0157 (1962/124968) while in subpopulation AFR AF= 0.0506 (1607/31776). AF 95% confidence interval is 0.0485. There are 38 homozygotes in gnomad4. There are 946 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.802-3del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1321-3del		splice_polypyrimidine_tract_variant, intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.212-3del		splice_polypyrimidine_tract_variant, intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.802-3del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 1955 AN: 124972 Hom.: 37 Cov.: 26

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00228

Gnomad EAS AF: 0.00170

Gnomad SAS AF: 0.00123

Gnomad FIN AF: 0.00825

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.0151

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.198 AC: 219315 AN: 1107958 Hom.: 2 Cov.: 0 AF XY: 0.200 AC XY: 109688 AN XY: 549778

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.0157 AC: 1962 AN: 124968 Hom.: 38 Cov.: 26 AF XY: 0.0157 AC XY: 946 AN XY: 60334

Gnomad4 AFR AF: 0.0506

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00228

Gnomad4 EAS AF: 0.00171

Gnomad4 SAS AF: 0.000992

Gnomad4 FIN AF: 0.00825

Gnomad4 NFE AF: 0.00298

Gnomad4 OTH AF: 0.0151

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2016	c.802-3delT in intron 7 of PTEN: This variant is not expected to have clinical s ignificance because it has been identified in 33.66% (3462/10286) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs771859047). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 19, 2016	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2020	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 21, 2021

- -

PTEN hamartoma tumor syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2015

- -

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;