rs121913293

Positions:

• chr10-87952142-C-A
• chr10-87952142-C-G
• chr10-87952142-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000314.8(PTEN):​c.517C>A​(p.Arg173Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 15) in uniprot entity PTEN_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87952142-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ 3.4883 (greater than the threshold 3.09). Trascript score misZ 4.1129 (greater than threshold 3.09). GenCC has associacion of gene with Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.517C>A	p.Arg173Ser	missense_variant	6/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1036C>A	p.Arg346Ser	missense_variant	7/10		NP_001291646.4
PTEN	NM_001304718.2	c.-75C>A		5_prime_UTR_variant	6/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.517C>A	p.Arg173Ser	missense_variant	6/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461008 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2016

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PTEN-related disease. This sequence change replaces arginine with serine at codon 173 of the PTEN protein (p.Arg173Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.84		Loss of stability (P = 0.0244);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

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: rs121913293; hg19: chr10-89711899;