Genetic Variant AKT3:c.46+3654G>A (chr1-243839471-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005465.7(AKT3):c.46+3654G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 151,994 control chromosomes in the GnomAD database, including 23,522 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 23522 hom., cov: 32)

Consequence

AKT3
NM_005465.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.71

Publications

4 publications found

Variant links:

Genes affected

AKT3 (HGNC:393): (AKT serine/threonine kinase 3) The protein encoded by this gene is a member of the AKT, also called PKB, serine/threonine protein kinase family. AKT kinases are known to be regulators of cell signaling in response to insulin and growth factors. They are involved in a wide variety of biological processes including cell proliferation, differentiation, apoptosis, tumorigenesis, as well as glycogen synthesis and glucose uptake. This kinase has been shown to be stimulated by platelet-derived growth factor (PDGF), insulin, and insulin-like growth factor 1 (IGF1). Alternatively splice transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

AKT3 Gene-Disease associations (from GenCC):

overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1
Inheritance: AD Classification: STRONG Submitted by: G2P
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
Inheritance: AD Classification: STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
microcephaly
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

AKT3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005465.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AKT3	NM_005465.7	MANE Select	c.46+3654G>A	intron	N/A	NP_005456.1	Q9Y243-1
AKT3	NM_001370074.1		c.46+3654G>A	intron	N/A	NP_001357003.1	Q9Y243-1
AKT3	NM_001206729.2		c.46+3654G>A	intron	N/A	NP_001193658.1	Q9Y243-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AKT3	ENST00000673466.1	MANE Select	c.46+3654G>A	intron	N/A	ENSP00000500582.1	Q9Y243-1
AKT3	ENST00000263826.12	TSL:1	c.46+3654G>A	intron	N/A	ENSP00000263826.5	Q9Y243-1
AKT3	ENST00000336199.9	TSL:1	c.46+3654G>A	intron	N/A	ENSP00000336943.5	Q9Y243-2

Frequencies

GnomAD3 genomes

AF:

0.506

AC:

76789

AN:

151876

Hom.:

23520

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.730

Gnomad AMR

AF:

0.601

Gnomad ASJ

AF:

0.749

Gnomad EAS

AF:

0.421

Gnomad SAS

AF:

0.467

Gnomad FIN

AF:

0.599

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.678

Gnomad OTH

AF:

0.549

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.505

AC:

76790

AN:

151994

Hom.:

23522

Cov.:

AF XY:

0.502

AC XY:

37330

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.150

AC:

6200

AN:

41458

American (AMR)

AF:

0.600

AC:

9168

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.749

AC:

2599

AN:

3470

East Asian (EAS)

AF:

0.421

AC:

2169

AN:

5156

South Asian (SAS)

AF:

0.467

AC:

2246

AN:

4812

European-Finnish (FIN)

AF:

0.599

AC:

6318

AN:

10554

Middle Eastern (MID)

AF:

0.619

AC:

182

AN:

294

European-Non Finnish (NFE)

AF:

0.678

AC:

46088

AN:

67962

Other (OTH)

AF:

0.548

AC:

1157

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1551

3103

4654

6206

7757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

646

1292

1938

2584

3230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.555

Hom.:

3726

Bravo

AF:

0.488

Asia WGS

AF:

0.393

AC:

1369

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.43

(source)

DANN

Benign

0.43

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over