10-87884469-C-G

Variant names:

• chr10-87884469-C-G
• rs35323240
• NM_000314.8:c.80-9556C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000314.8(PTEN):​c.80-9556C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 151,558 control chromosomes in the GnomAD database, including 2,310 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2310 hom., cov: 32)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.80-9556C>G		intron_variant	Intron 1 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.599-9556C>G		intron_variant	Intron 2 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.-626-9556C>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.80-9556C>G		intron_variant	Intron 1 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23729 AN: 151440 Hom.: 2308 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.148

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

GnomAD4 genome AF: 0.157 AC: 23725 AN: 151558 Hom.: 2310 Cov.: 32 AF XY: 0.162 AC XY: 11984 AN XY: 74034

African (AFR) AF: 0.0370 AC: 1533 AN: 41386

American (AMR) AF: 0.192 AC: 2915 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 538 AN: 3466

East Asian (EAS) AF: 0.174 AC: 902 AN: 5178

South Asian (SAS) AF: 0.275 AC: 1326 AN: 4814

European-Finnish (FIN) AF: 0.253 AC: 2645 AN: 10466

Middle Eastern (MID) AF: 0.122 AC: 35 AN: 288

European-Non Finnish (NFE) AF: 0.197 AC: 13352 AN: 67732

Other (OTH) AF: 0.146 AC: 307 AN: 2104

Alfa AF: 0.107 Hom.: 175

Bravo AF: 0.145

Asia WGS AF: 0.210 AC: 716 AN: 3424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.83
DANN	Benign	0.56
PhyloP100		0.30
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: rs35323240; hg19: chr10-89644226;