NM_000314.8:c.802-6_802-3dupTTTT

Variant names:

• chr10-87960876-C-CTTTT
• rs34003473
• NM_000314.8:c.802-6_802-3dupTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PVS1_Strong BP6_Very_Strong BS1

The NM_000314.8(PTEN):​c.802-6_802-3dupTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000702 in 1,425,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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: Genomics England PanelApp, Ambry Genetics, G2P, 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

Our verdict: Benign. The variant received -8 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.
• BP6: Variant 10-87960876-C-CTTTT is Benign according to our data. Variant chr10-87960876-C-CTTTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3075885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000248 (31/125124) while in subpopulation AFR AF = 0.000975 (31/31790). AF 95% confidence interval is 0.000705. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

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.802-6_802-3dupTTTT		splice_acceptor intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.1321-6_1321-3dupTTTT		splice_acceptor intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.211-6_211-3dupTTTT		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_802-17insTTTT		intron	N/A	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1321-18_1321-17insTTTT		intron	N/A	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.895-18_895-17insTTTT		intron	N/A	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 30 AN: 125128 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000945

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000531 AC: 69 AN: 1299994 Hom.: 0 Cov.: 0 AF XY: 0.0000494 AC XY: 32 AN XY: 647278

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

African (AFR) AF: 0.00102 AC: 27 AN: 26354

American (AMR) AF: 0.000153 AC: 5 AN: 32666

Ashkenazi Jewish (ASJ) AF: 0.0000426 AC: 1 AN: 23500

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35686

South Asian (SAS) AF: 0.0000140 AC: 1 AN: 71362

European-Finnish (FIN) AF: 0.0000214 AC: 1 AN: 46630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4952

European-Non Finnish (NFE) AF: 0.0000269 AC: 27 AN: 1005190

Other (OTH) AF: 0.000112 AC: 6 AN: 53654

⚠️ 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: 0.000248 AC: 31 AN: 125124 Hom.: 0 Cov.: 26 AF XY: 0.000199 AC XY: 12 AN XY: 60428

African (AFR) AF: 0.000975 AC: 31 AN: 31790

American (AMR) AF: 0.00 AC: 0 AN: 12986

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4682

South Asian (SAS) AF: 0.00 AC: 0 AN: 4034

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 58860

Other (OTH) AF: 0.00 AC: 0 AN: 1724

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cowden syndrome 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs34003473; hg19: chr10-89720633;