rs3730358

Variant names:

• chr14-104780070-G-A
• rs3730358
• NM_001382430.1:c.175+18C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.87
• Publications: 63 publications found

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 Gene-Disease associations (from GenCC):

• Proteus syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 6

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1284750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
AKT1	NM_001382430.1	c.175+18C>T		intron_variant	Intron 4 of 14	ENST00000649815.2	NP_001369359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1	ENST00000649815.2	c.175+18C>T		intron_variant	Intron 4 of 14		NM_001382430.1	ENSP00000497822.1

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

GnomAD2 exomes AF: 0.160 AC: 39847 AN: 249250 AF XY: 0.160

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 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

African (AFR) AF: 0.211 AC: 7061 AN: 33404

American (AMR) AF: 0.229 AC: 10158 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 4125 AN: 26042

East Asian (EAS) AF: 0.0867 AC: 3435 AN: 39628

South Asian (SAS) AF: 0.189 AC: 16260 AN: 86148

European-Finnish (FIN) AF: 0.119 AC: 6287 AN: 52718

Middle Eastern (MID) AF: 0.152 AC: 872 AN: 5746

European-Non Finnish (NFE) AF: 0.149 AC: 165916 AN: 1110018

Other (OTH) AF: 0.149 AC: 8996 AN: 60226

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

African (AFR) AF: 0.204 AC: 8491 AN: 41540

American (AMR) AF: 0.199 AC: 3037 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 591 AN: 3472

East Asian (EAS) AF: 0.0676 AC: 350 AN: 5174

South Asian (SAS) AF: 0.187 AC: 900 AN: 4824

European-Finnish (FIN) AF: 0.128 AC: 1360 AN: 10608

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10175 AN: 68018

Other (OTH) AF: 0.161 AC: 340 AN: 2112

Alfa AF: 0.141 Hom.: 1002

Bravo AF: 0.176

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cowden syndrome 6 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.29
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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