chr14-104770411-A-G

Position:

chr14-104770411-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting

The NM_001382430.1(AKT1):c.1373T>C(p.Met458Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,611,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. M458K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

AKT1
NM_001382430.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 9.19

Variant links:

Genes affected

AKT1 (HGNC:391): (AKT serine/threonine kinase 1) This gene encodes one of the three members of the human AKT serine-threonine protein kinase family which are often referred to as protein kinase B alpha, beta, and gamma. These highly similar AKT proteins all have an N-terminal pleckstrin homology domain, a serine/threonine-specific kinase domain and a C-terminal regulatory domain. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT/PI3K forms a key component of many signalling pathways that involve the binding of membrane-bound ligands such as receptor tyrosine kinases, G-protein coupled receptors, and integrin-linked kinase. These AKT proteins therefore regulate a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. AKT proteins are recruited to the cell membrane by phosphatidylinositol 3,4,5-trisphosphate (PIP3) after phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) by PI3K. Subsequent phosphorylation of both threonine residue 308 and serine residue 473 is required for full activation of the AKT1 protein encoded by this gene. Phosphorylation of additional residues also occurs, for example, in response to insulin growth factor-1 and epidermal growth factor. Protein phosphatases act as negative regulators of AKT proteins by dephosphorylating AKT or PIP3. The PI3K/AKT signalling pathway is crucial for tumor cell survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating AKT1 which then phosphorylates and inactivates components of the apoptotic machinery. AKT proteins also participate in the mammalian target of rapamycin (mTOR) signalling pathway which controls the assembly of the eukaryotic translation initiation factor 4F (eIF4E) complex and this pathway, in addition to responding to extracellular signals from growth factors and cytokines, is disregulated in many cancers. Mutations in this gene are associated with multiple types of cancer and excessive tissue growth including Proteus syndrome and Cowden syndrome 6, and breast, colorectal, and ovarian cancers. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]

AKT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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), AKT1. . Gene score misZ 3.4778 (greater than the threshold 3.09). Trascript score misZ 4.2155 (greater than threshold 3.09). GenCC has associacion of gene with Proteus syndrome, Cowden disease, Cowden syndrome 6.

BP4

Computational evidence support a benign effect (MetaRNN=0.14931205).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000526 (8/152194) while in subpopulation EAS AF= 0.000771 (4/5190). AF 95% confidence interval is 0.000263. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT1	NM_001382430.1 linkuse as main transcript	c.1373T>C	p.Met458Thr	missense_variant	15/15	ENST00000649815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT1	ENST00000649815.2 linkuse as main transcript	c.1373T>C	p.Met458Thr	missense_variant	15/15		NM_001382430.1	P1	P31749-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000453

AC:

AN:

242576

Hom.:

AF XY:

0.0000607

AC XY:

AN XY:

131724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000605

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1459110

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

725692

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00106

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cowden syndrome 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 458 of the AKT1 protein (p.Met458Thr). This variant is present in population databases (rs587778018, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with AKT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 133454). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.53

D;D;D;D;D;D;D

Eigen

Benign

-0.11

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.57

.;.;.;.;.;.;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.15

T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

M;M;M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.6

D;D;D;D;D;.;D

REVEL

Benign

0.14

Sift

Benign

0.080

T;T;T;T;T;.;T

Sift4G

Benign

0.33

T;T;T;T;T;.;T

Polyphen

0.0030

B;B;B;B;B;B;B

Vest4

0.61

MutPred

0.34

Gain of glycosylation at S457 (P = 0.0171);Gain of glycosylation at S457 (P = 0.0171);Gain of glycosylation at S457 (P = 0.0171);Gain of glycosylation at S457 (P = 0.0171);Gain of glycosylation at S457 (P = 0.0171);Gain of glycosylation at S457 (P = 0.0171);Gain of glycosylation at S457 (P = 0.0171);

MVP

0.51

MPC

0.79

ClinPred

0.30

GERP RS

4.4

Varity_R

0.67

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over