10-87960876-CTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr10-87960876-C-CTTTTTTTTTTT
• rs34003473
• NM_000314.8:c.802-13_802-3dupTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_000314.8(PTEN):​c.802-13_802-3dupTTTTTTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,425,206 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene PTEN is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000080 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 7 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, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

Specifications for PTEN are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.18564357 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.802-13_802-3dupTTTTTTTTTTT		splice_acceptor intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.1321-13_1321-3dupTTTTTTTTTTT		splice_acceptor intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.211-13_211-3dupTTTTTTTTTTT		splice_acceptor intron	N/A	NP_001291647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.802-18_802-17insTTTTTTTTTTT		intron	N/A	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1321-18_1321-17insTTTTTTTTTTT		intron	N/A	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.895-18_895-17insTTTTTTTTTTT		intron	N/A	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes AF: 0.00000799 AC: 1 AN: 125122 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000262 AC: 34 AN: 1300084 Hom.: 0 Cov.: 0 AF XY: 0.0000324 AC XY: 21 AN XY: 647340

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000114 AC: 3 AN: 26380

American (AMR) AF: 0.0000306 AC: 1 AN: 32666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23502

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35690

South Asian (SAS) AF: 0.0000981 AC: 7 AN: 71374

European-Finnish (FIN) AF: 0.0000214 AC: 1 AN: 46632

Middle Eastern (MID) AF: 0.000202 AC: 1 AN: 4954

European-Non Finnish (NFE) AF: 0.0000179 AC: 18 AN: 1005234

Other (OTH) AF: 0.0000186 AC: 1 AN: 53652

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000799 AC: 1 AN: 125122 Hom.: 0 Cov.: 26 AF XY: 0.0000166 AC XY: 1 AN XY: 60400

African (AFR) AF: 0.00 AC: 0 AN: 31732

American (AMR) AF: 0.00 AC: 0 AN: 12970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3076

East Asian (EAS) AF: 0.000213 AC: 1 AN: 4698

South Asian (SAS) AF: 0.00 AC: 0 AN: 4064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 58866

Other (OTH) AF: 0.00 AC: 0 AN: 1720

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34003473;

hg19: chr10-89720633;