chr10-87960876-C-CTT

Variant names:

• chr10-87960876-C-CTT
• rs34003473
• NM_000314.8:c.802-4_802-3dupTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BS1 BS2

The NM_000314.8(PTEN):​c.802-4_802-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.007 in 1,415,296 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 26)
  • Exomes 𝑓: 0.0073 (1 hom.)
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• 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 -12 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: ctttttttttttttttttAGgac. 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-CTT is Benign according to our data. Variant chr10-87960876-C-CTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00336 (420/125120) while in subpopulation SAS AF = 0.0216 (87/4032). AF 95% confidence interval is 0.0179. There are 3 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD 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.802-4_802-3dupTT		splice_acceptor intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.1321-4_1321-3dupTT		splice_acceptor intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.211-4_211-3dupTT		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_802-17insTT		intron	N/A	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1321-18_1321-17insTT		intron	N/A	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.895-18_895-17insTT		intron	N/A	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 421 AN: 125124 Hom.: 3 Cov.: 26

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00193

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.000144

Gnomad MID AF: 0.00403

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00465

GnomAD2 exomes AF: 0.0116 AC: 1341 AN: 115828 AF XY: 0.0113

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.0305

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00742

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00735 AC: 9481 AN: 1290176 Hom.: 1 Cov.: 0 AF XY: 0.00751 AC XY: 4826 AN XY: 642262

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

African (AFR) AF: 0.00588 AC: 154 AN: 26180

American (AMR) AF: 0.0118 AC: 382 AN: 32340

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 380 AN: 23246

East Asian (EAS) AF: 0.0155 AC: 546 AN: 35268

South Asian (SAS) AF: 0.0189 AC: 1329 AN: 70328

European-Finnish (FIN) AF: 0.00306 AC: 142 AN: 46370

Middle Eastern (MID) AF: 0.00711 AC: 35 AN: 4924

European-Non Finnish (NFE) AF: 0.00603 AC: 6023 AN: 998290

Other (OTH) AF: 0.00921 AC: 490 AN: 53230

⚠️ 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: 0.00336 AC: 420 AN: 125120 Hom.: 3 Cov.: 26 AF XY: 0.00344 AC XY: 208 AN XY: 60424

African (AFR) AF: 0.00129 AC: 41 AN: 31790

American (AMR) AF: 0.00192 AC: 25 AN: 12988

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 71 AN: 3076

East Asian (EAS) AF: 0.0107 AC: 50 AN: 4682

South Asian (SAS) AF: 0.0216 AC: 87 AN: 4032

European-Finnish (FIN) AF: 0.000144 AC: 1 AN: 6934

Middle Eastern (MID) AF: 0.00446 AC: 1 AN: 224

European-Non Finnish (NFE) AF: 0.00231 AC: 136 AN: 58856

Other (OTH) AF: 0.00464 AC: 8 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
-	-	6	not specified (6)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Cowden syndrome 1 (1)
-	-	1	Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C2931456:Familial prostate cancer;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 (1)
-	-	1	Prostate cancer;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 (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;