10-87863648-G-C

Position:

• chr10-87863648-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000692337.1(ENSG00000289051):​c.90G>C​(p.Gln30His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENSG00000289051 ENST00000692337.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

Genes affected

ENSG00000289051 (HGNC:55481):

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.-822G>C		5_prime_UTR_variant	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.-302G>C		5_prime_UTR_variant	1/10		NP_001291646.4
PTEN	NM_001304718.2	c.-1527G>C		5_prime_UTR_variant	1/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000289051	ENST00000692337.1	c.90G>C	p.Gln30His	missense_variant	1/1			ENSP00000509326.1
PTEN	ENST00000371953	c.-822G>C		5_prime_UTR_variant	1/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2014

This variant is denoted PTEN c.-822G>C, and describes a nucleotide substitution 822 base pairs upstream of the ATG translational start site in the PTEN core promoter region. The surrounding sequence, with the base that is substituted in brackets, is tgca[g/c]ccat. This variant has not been published in the literature to our knowledge. This variant occurs within a region of the PTEN core promoter (c.-798 to c.-1238) in which published pathogenic promoter variants are located. Furthermore, Zhou et al. (2003) reported that approximately 9% (9/95) of patients with Cowden syndrome were found to carry a point variant in the PTEN core promoter region. At this time, we consider this to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Benign	0.95

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: rs587779993; hg19: chr10-89623405;