1-243831739-T-C

Variant names:

• chr1-243831739-T-C
• rs10157763
• NM_005465.7:c.46+11386A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005465.7(AKT3):​c.46+11386A>G 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 151,822 control chromosomes in the GnomAD database, including 23,534 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 (23534 hom., cov: 30)
• Consequence: AKT3 NM_005465.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.134
• Publications: 8 publications found

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: Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae)
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• microcephaly

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT3	NM_005465.7	c.46+11386A>G		intron_variant	Intron 2 of 13	ENST00000673466.1	NP_005456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT3	ENST00000673466.1	c.46+11386A>G		intron_variant	Intron 2 of 13		NM_005465.7	ENSP00000500582.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76742 AN: 151704 Hom.: 23532 Cov.: 30

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.747

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.679

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: 76743 AN: 151822 Hom.: 23534 Cov.: 30 AF XY: 0.502 AC XY: 37265 AN XY: 74164

African (AFR) AF: 0.149 AC: 6180 AN: 41406

American (AMR) AF: 0.601 AC: 9161 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2588 AN: 3464

East Asian (EAS) AF: 0.420 AC: 2161 AN: 5144

South Asian (SAS) AF: 0.468 AC: 2246 AN: 4804

European-Finnish (FIN) AF: 0.598 AC: 6277 AN: 10502

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.679 AC: 46130 AN: 67940

Other (OTH) AF: 0.548 AC: 1155 AN: 2108

Alfa AF: 0.625 Hom.: 68446

Bravo AF: 0.488

Asia WGS AF: 0.394 AC: 1373 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.85
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10157763; hg19: chr1-243995041;