rs12573787

Positions:

• chr10-87863959-G-A
• chr10-87863959-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2 BP4_Moderate BP6_Very_Strong BA1

The NM_001304717.5(PTEN):​c.10G>A​(p.Gly4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 381,510 control chromosomes in the GnomAD database, including 4,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1493 hom., cov: 31)
  • Exomes 𝑓: 0.15 (3333 hom.)
• Consequence: PTEN NM_001304717.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:8
• Conservation: PhyloP100: 2.14

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 -17 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ 3.4883 (greater than the threshold 3.09). Trascript score misZ 4.001 (greater than threshold 3.09). GenCC has associacion of gene with Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 10-87863959-G-A is Benign according to our data. Variant chr10-87863959-G-A is described in ClinVar as [Benign]. Clinvar id is 810888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87863959-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.-511G>A		5_prime_UTR_variant	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.10G>A	p.Gly4Arg	missense_variant	1/10		NP_001291646.4
PTEN	NM_001304718.2	c.-1216G>A		5_prime_UTR_variant	1/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953	c.-511G>A		5_prime_UTR_variant	1/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 18970 AN: 150292 Hom.: 1491 Cov.: 31

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.154 AC: 35529 AN: 231108 Hom.: 3333 Cov.: 0 AF XY: 0.152 AC XY: 18136 AN XY: 119532

Gnomad4 AFR exome AF: 0.0618

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.349

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.126 AC: 18981 AN: 150402 Hom.: 1493 Cov.: 31 AF XY: 0.127 AC XY: 9318 AN XY: 73528

Gnomad4 AFR AF: 0.0615

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.349

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.138

Alfa AF: 0.0599 Hom.: 63

Bravo AF: 0.131

Asia WGS AF: 0.212 AC: 730 AN: 3438

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 36. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Myeloproliferative neoplasm, unclassifiable Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

Aug 25, 2022

- -

PTEN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

PTEN hamartoma tumor syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12573787; hg19: chr10-89623716;