10-87893929-A-G

Variant names:

• chr10-87893929-A-G
• rs1903858
• NM_000314.8:c.80-96A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000314.8(PTEN):​c.80-96A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 896,268 control chromosomes in the GnomAD database, including 58,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11905 hom., cov: 31)
  • Exomes 𝑓: 0.34 (46285 hom.)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.751
• Publications: 26 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 10-87893929-A-G is Benign according to our data. Variant chr10-87893929-A-G is described in ClinVar as Benign. ClinVar VariationId is 440219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.80-96A>G		intron_variant	Intron 1 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.599-96A>G		intron_variant	Intron 2 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.-626-96A>G		intron_variant	Intron 1 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.80-96A>G		intron_variant	Intron 1 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.387 AC: 57488 AN: 148358 Hom.: 11868 Cov.: 31

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.445

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.342 AC: 255591 AN: 747792 Hom.: 46285 AF XY: 0.338 AC XY: 132741 AN XY: 392880

African (AFR) AF: 0.469 AC: 8836 AN: 18822

American (AMR) AF: 0.454 AC: 15155 AN: 33400

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 7068 AN: 19468

East Asian (EAS) AF: 0.501 AC: 16550 AN: 33014

South Asian (SAS) AF: 0.303 AC: 19864 AN: 65550

European-Finnish (FIN) AF: 0.326 AC: 12568 AN: 38512

Middle Eastern (MID) AF: 0.388 AC: 1250 AN: 3224

European-Non Finnish (NFE) AF: 0.323 AC: 161455 AN: 500220

Other (OTH) AF: 0.361 AC: 12845 AN: 35582

GnomAD4 genome AF: 0.388 AC: 57574 AN: 148476 Hom.: 11905 Cov.: 31 AF XY: 0.387 AC XY: 28054 AN XY: 72584

African (AFR) AF: 0.472 AC: 19457 AN: 41208

American (AMR) AF: 0.446 AC: 6633 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1282 AN: 3406

East Asian (EAS) AF: 0.507 AC: 2621 AN: 5166

South Asian (SAS) AF: 0.298 AC: 1432 AN: 4798

European-Finnish (FIN) AF: 0.337 AC: 3438 AN: 10200

Middle Eastern (MID) AF: 0.434 AC: 125 AN: 288

European-Non Finnish (NFE) AF: 0.328 AC: 21513 AN: 65566

Other (OTH) AF: 0.403 AC: 825 AN: 2046

Alfa AF: 0.340 Hom.: 11930

Bravo AF: 0.393

Asia WGS AF: 0.443 AC: 1538 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 06, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 32% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.59
DANN	Benign	0.69
PhyloP100		-0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1903858; hg19: chr10-89653686; COSMIC: COSV64292778;