chr10-87960933-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_000314.8(PTEN):​c.841C>A​(p.Pro281Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Consequence

PTEN
NM_000314.8 missense

Scores

3
10
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.54
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTENNM_000314.8 linkuse as main transcriptc.841C>A p.Pro281Thr missense_variant 8/9 ENST00000371953.8 NP_000305.3
PTENNM_001304717.5 linkuse as main transcriptc.1360C>A p.Pro454Thr missense_variant 9/10 NP_001291646.4
PTENNM_001304718.2 linkuse as main transcriptc.250C>A p.Pro84Thr missense_variant 8/9 NP_001291647.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTENENST00000371953.8 linkuse as main transcriptc.841C>A p.Pro281Thr missense_variant 8/91 NM_000314.8 ENSP00000361021 P1P60484-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
25
DANN
Benign
0.94
DEOGEN2
Uncertain
0.65
D;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Uncertain
0.61
D;D
MetaSVM
Uncertain
-0.065
T
MutationAssessor
Benign
1.6
L;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.1
N;.
REVEL
Uncertain
0.57
Sift
Benign
0.35
T;.
Sift4G
Benign
0.61
T;T
Polyphen
0.66
P;.
Vest4
0.81
MutPred
0.49
Loss of glycosylation at P281 (P = 0.0874);.;
MVP
0.94
MPC
1.3
ClinPred
0.73
D
GERP RS
5.1
Varity_R
0.39
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-89720690; API