Genetic Variant PTEN:c.493-6446G>C (chr10-87945672-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000314.8(PTEN):c.493-6446G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 357,044 control chromosomes in the GnomAD database, including 25,190 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 0.39 ( 12006 hom., cov: 32)

Exomes 𝑓: 0.35 ( 13184 hom. )

Consequence

PTEN
NM_000314.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.05

Publications

29 publications found

Variant links:

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 links:

RPL11P3 (HGNC:36342): (ribosomal protein L11 pseudogene 3)

RPL11P3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PTEN	NM_000314.8	MANE Select	c.493-6446G>C	intron	N/A	NP_000305.3
PTEN	NM_001304717.5		c.1012-6446G>C	intron	N/A	NP_001291646.4
PTEN	NM_001304718.2		c.-100+2903G>C	intron	N/A	NP_001291647.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PTEN	ENST00000371953.8	TSL:1 MANE Select	c.493-6446G>C	intron	N/A	ENSP00000361021.3	P60484-1
PTEN	ENST00000693560.1		c.1012-6446G>C	intron	N/A	ENSP00000509861.1	A0A8I5KSF9
PTEN	ENST00000700029.2		c.493-6446G>C	intron	N/A	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes

AF:

0.390

AC:

59296

AN:

151936

Hom.:

11970

Cov.:

show subpopulations

Gnomad AFR

AF:

0.471

Gnomad AMI

AF:

0.270

Gnomad AMR

AF:

0.449

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.506

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.403

GnomAD4 exome

AF:

0.351

AC:

71960

AN:

204990

Hom.:

13184

Cov.:

AF XY:

0.343

AC XY:

40001

AN XY:

116750

show subpopulations

African (AFR)

AF:

0.476

AC:

2365

AN:

4968

American (AMR)

AF:

0.461

AC:

6373

AN:

13838

Ashkenazi Jewish (ASJ)

AF:

0.383

AC:

1732

AN:

4518

East Asian (EAS)

AF:

0.496

AC:

4504

AN:

9084

South Asian (SAS)

AF:

0.300

AC:

10652

AN:

35464

European-Finnish (FIN)

AF:

0.341

AC:

3773

AN:

11062

Middle Eastern (MID)

AF:

0.364

AC:

258

AN:

708

European-Non Finnish (NFE)

AF:

0.334

AC:

38546

AN:

115246

Other (OTH)

AF:

0.372

AC:

3757

AN:

10102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

2155

4310

6466

8621

10776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.391

AC:

59380

AN:

152054

Hom.:

12006

Cov.:

AF XY:

0.389

AC XY:

28927

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.471

AC:

19540

AN:

41444

American (AMR)

AF:

0.449

AC:

6865

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

1305

AN:

3472

East Asian (EAS)

AF:

0.505

AC:

2613

AN:

5170

South Asian (SAS)

AF:

0.294

AC:

1420

AN:

4824

European-Finnish (FIN)

AF:

0.345

AC:

3645

AN:

10570

Middle Eastern (MID)

AF:

0.438

AC:

128

AN:

292

European-Non Finnish (NFE)

AF:

0.335

AC:

22754

AN:

67978

Other (OTH)

AF:

0.409

AC:

864

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1831

3663

5494

7326

9157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

548

1096

1644

2192

2740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.193

Hom.:

354

Bravo

AF:

0.403

Asia WGS

AF:

0.442

AC:

1539

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.41

(source)

DANN

Benign

0.47

PhyloP100

3.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over