10-87966988-T-C

Position:

• chr10-87966988-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000314.8(PTEN):​c.*1516T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 218,680 control chromosomes in the GnomAD database, including 15,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9528 hom., cov: 24)
  • Exomes 𝑓: 0.39 (5779 hom.)
• Consequence: PTEN NM_000314.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 10-87966988-T-C is Benign according to our data. Variant chr10-87966988-T-C is described in ClinVar as [Benign]. Clinvar id is 301463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.*1516T>C		3_prime_UTR_variant	9/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.*1516T>C		3_prime_UTR_variant	10/10		NP_001291646.4
PTEN	NM_001304718.2	c.*1516T>C		3_prime_UTR_variant	9/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.*1516T>C		3_prime_UTR_variant	9/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.341 AC: 49462 AN: 145100 Hom.: 9530 Cov.: 24

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.276

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.394 AC: 28976 AN: 73494 Hom.: 5779 Cov.: 0 AF XY: 0.398 AC XY: 13549 AN XY: 34062

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.350

Gnomad4 ASJ exome AF: 0.361

Gnomad4 EAS exome AF: 0.431

Gnomad4 SAS exome AF: 0.653

Gnomad4 FIN exome AF: 0.515

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.341 AC: 49456 AN: 145186 Hom.: 9528 Cov.: 24 AF XY: 0.349 AC XY: 24459 AN XY: 70168

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.447

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.319

Alfa AF: 0.267 Hom.: 1106

Bravo AF: 0.320

Asia WGS AF: 0.470 AC: 1624 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs701848; hg19: chr10-89726745; COSMIC: COSV64293119;