10-87960876-CTTTTTTTTT-CTTTTTTTT

Variant names:

• chr10-87960876-CT-C
• rs34003473
• NM_000314.8:c.802-3delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000314.8(PTEN):​c.802-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 124,968 control chromosomes in the GnomAD database, including 38 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene PTEN is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.016 (38 hom., cov: 26)
  • Exomes 𝑓: 0.20 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• 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

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 10-87960876-CT-C is Benign according to our data. Variant chr10-87960876-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 229653.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 = 0.0157 (1962/124968) while in subpopulation AFR AF = 0.0506 (1607/31776). AF 95% confidence interval is 0.0485. There are 38 homozygotes in GnomAd4. There are 946 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AD,AR gene

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.802-3delT		splice_region intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.1321-3delT		splice_region intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.211-3delT		splice_region 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.802-17delT		intron	N/A	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1321-17delT		intron	N/A	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.895-17delT		intron	N/A	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 1955 AN: 124972 Hom.: 37 Cov.: 26

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00228

Gnomad EAS AF: 0.00170

Gnomad SAS AF: 0.00123

Gnomad FIN AF: 0.00825

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.0151

GnomAD2 exomes AF: 0.276 AC: 31954 AN: 115828 AF XY: 0.282

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.273

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.198 AC: 219315 AN: 1107958 Hom.: 2 Cov.: 0 AF XY: 0.200 AC XY: 109688 AN XY: 549778

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

African (AFR) AF: 0.218 AC: 5004 AN: 22918

American (AMR) AF: 0.193 AC: 5670 AN: 29414

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 4568 AN: 19984

East Asian (EAS) AF: 0.128 AC: 4091 AN: 32028

South Asian (SAS) AF: 0.209 AC: 12731 AN: 60804

European-Finnish (FIN) AF: 0.235 AC: 9232 AN: 39206

Middle Eastern (MID) AF: 0.212 AC: 873 AN: 4114

European-Non Finnish (NFE) AF: 0.197 AC: 168027 AN: 853502

Other (OTH) AF: 0.198 AC: 9119 AN: 45988

⚠️ 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: 0.0157 AC: 1962 AN: 124968 Hom.: 38 Cov.: 26 AF XY: 0.0157 AC XY: 946 AN XY: 60334

African (AFR) AF: 0.0506 AC: 1607 AN: 31776

American (AMR) AF: 0.00601 AC: 78 AN: 12978

Ashkenazi Jewish (ASJ) AF: 0.00228 AC: 7 AN: 3074

East Asian (EAS) AF: 0.00171 AC: 8 AN: 4680

South Asian (SAS) AF: 0.000992 AC: 4 AN: 4034

European-Finnish (FIN) AF: 0.00825 AC: 57 AN: 6910

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

European-Non Finnish (NFE) AF: 0.00298 AC: 175 AN: 58754

Other (OTH) AF: 0.0151 AC: 26 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
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	PTEN hamartoma tumor syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

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: rs34003473; hg19: chr10-89720633; COSMIC: COSV64293422;