rs3730358

Positions:

• chr14-104780070-G-A
• chr14-104780070-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001382430.1(AKT1):​c.175+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,610,612 control chromosomes in the GnomAD database, including 19,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2164 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17769 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.87

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-104780070-G-A is Benign according to our data. Variant chr14-104780070-G-A is described in ClinVar as [Benign]. Clinvar id is 1284750.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-104780070-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT1	NM_001382430.1	c.175+18C>T		intron_variant		ENST00000649815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT1	ENST00000649815.2	c.175+18C>T		intron_variant			NM_001382430.1	P1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25420 AN: 152120 Hom.: 2164 Cov.: 33

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.160 AC: 39847 AN: 249250 Hom.: 3567 AF XY: 0.160 AC XY: 21589 AN XY: 134964

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.0630

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.153 AC: 223110 AN: 1458374 Hom.: 17769 Cov.: 32 AF XY: 0.154 AC XY: 111748 AN XY: 725196

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.0867

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.167 AC: 25426 AN: 152238 Hom.: 2164 Cov.: 33 AF XY: 0.166 AC XY: 12363 AN XY: 74438

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.199

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.0676

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.161

Alfa AF: 0.122 Hom.: 420

Bravo AF: 0.176

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cowden syndrome 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.29

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: rs3730358; hg19: chr14-105246407; COSMIC: COSV62574042; COSMIC: COSV62574042;