rs3730344

Variant names:

• chr14-104775239-G-A
• rs3730344
• NM_001382430.1:c.436-32C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-104775239-G-A
• chr14-104775239-G-C

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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.46
• Publications: 9 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, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1261565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382430.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	NM_001382430.1	MANE Select	c.436-32C>T		intron	N/A	NP_001369359.1	B0LPE5
	AKT1	NM_001014431.2		c.436-32C>T		intron	N/A	NP_001014431.1	B0LPE5
	AKT1	NM_001014432.2		c.436-32C>T		intron	N/A	NP_001014432.1	P31749-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1	ENST00000649815.2	MANE Select	c.436-32C>T		intron	N/A	ENSP00000497822.1	P31749-1
	AKT1	ENST00000349310.7	TSL:1	c.436-32C>T		intron	N/A	ENSP00000270202.4	P31749-1
	AKT1	ENST00000402615.6	TSL:1	c.436-32C>T		intron	N/A	ENSP00000385326.2	P31749-1

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

GnomAD2 exomes AF: 0.0322 AC: 7974 AN: 247580 AF XY: 0.0264

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 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

African (AFR) AF: 0.280 AC: 9376 AN: 33472

American (AMR) AF: 0.0451 AC: 2017 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00896 AC: 234 AN: 26128

East Asian (EAS) AF: 0.0140 AC: 557 AN: 39698

South Asian (SAS) AF: 0.0238 AC: 2049 AN: 86242

European-Finnish (FIN) AF: 0.00971 AC: 491 AN: 50582

Middle Eastern (MID) AF: 0.0290 AC: 167 AN: 5764

European-Non Finnish (NFE) AF: 0.00393 AC: 4366 AN: 1111864

Other (OTH) AF: 0.0249 AC: 1505 AN: 60374

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

African (AFR) AF: 0.270 AC: 11190 AN: 41488

American (AMR) AF: 0.0497 AC: 760 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.0140 AC: 72 AN: 5160

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4826

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10616

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00434 AC: 295 AN: 68028

Other (OTH) AF: 0.0662 AC: 140 AN: 2116

Alfa AF: 0.0403 Hom.: 239

Bravo AF: 0.0960

Asia WGS AF: 0.0400 AC: 138 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.019
DANN	Benign	0.63
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3730344; hg19: chr14-105241576; COSMIC: COSV62572311; COSMIC: COSV62572311;