10-87895485-CA-CAA

Variant names:

• chr10-87895485-C-CA
• rs3831732
• NM_000314.8:c.164+1382dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000314.8(PTEN):​c.164+1382dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (10335 hom., cov: 0)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.127
• Publications: 3 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.164+1382dupA		intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.683+1382dupA		intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.-542+1382dupA		intron	N/A	NP_001291647.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.164+1376_164+1377insA		intron	N/A	ENSP00000361021.3
	PTEN	ENST00000693560.1		c.683+1376_683+1377insA		intron	N/A	ENSP00000509861.1
	PTEN	ENST00000700029.2		c.164+1376_164+1377insA		intron	N/A	ENSP00000514759.2

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53399 AN: 151766 Hom.: 10331 Cov.: 0

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.335

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.352 AC: 53411 AN: 151884 Hom.: 10335 Cov.: 0 AF XY: 0.360 AC XY: 26734 AN XY: 74192

African (AFR) AF: 0.186 AC: 7705 AN: 41412

American (AMR) AF: 0.350 AC: 5343 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1181 AN: 3470

East Asian (EAS) AF: 0.426 AC: 2197 AN: 5158

South Asian (SAS) AF: 0.617 AC: 2973 AN: 4818

European-Finnish (FIN) AF: 0.462 AC: 4850 AN: 10506

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27920 AN: 67940

Other (OTH) AF: 0.331 AC: 699 AN: 2110

Alfa AF: 0.251 Hom.: 643

Bravo AF: 0.332

Asia WGS AF: 0.468 AC: 1619 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.13
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: rs3831732; hg19: chr10-89655242;