rs3730344

chr14-104775239-G-Achr14-104775239-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.436-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,611,036 control chromosomes in the GnomAD database, including 3,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.084 (1565 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1520 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.46

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=-0.93).
• BP6: Variant 14-104775239-G-A is Benign according to our data. Variant chr14-104775239-G-A is described in ClinVar as [Benign]. Clinvar id is 1261565.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKT1	NM_001382430.1	c.436-32C>T		intron_variant		ENST00000649815.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKT1	ENST00000649815.2	c.436-32C>T		intron_variant			NM_001382430.1	P1

Frequencies

GnomAD3 genomes AF: 0.0834 AC: 12691 AN: 152100 Hom.: 1563 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0495

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.0669

GnomAD3 exomes AF: 0.0322 AC: 7974 AN: 247580 Hom.: 686 AF XY: 0.0264 AC XY: 3547 AN XY: 134422

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.00848

Gnomad EAS exome AF: 0.0122

Gnomad SAS exome AF: 0.0251

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.0226

GnomAD4 exome AF: 0.0142 AC: 20762 AN: 1458818 Hom.: 1520 Cov.: 32 AF XY: 0.0136 AC XY: 9868 AN XY: 725886

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.0451

Gnomad4 ASJ exome AF: 0.00896

Gnomad4 EAS exome AF: 0.0140

Gnomad4 SAS exome AF: 0.0238

Gnomad4 FIN exome AF: 0.00971

Gnomad4 NFE exome AF: 0.00393

Gnomad4 OTH exome AF: 0.0249

GnomAD4 genome AF: 0.0836 AC: 12725 AN: 152218 Hom.: 1565 Cov.: 33 AF XY: 0.0821 AC XY: 6110 AN XY: 74416

Gnomad4 AFR AF: 0.270

Gnomad4 AMR AF: 0.0497

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.0140

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00434

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0412 Hom.: 135

Bravo AF: 0.0960

Asia WGS AF: 0.0400 AC: 138 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.019
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs3730344; hg19: chr14-105241576; COSMIC: COSV62572311; COSMIC: COSV62572311;