1-243693379-A-G

Variant names:

• chr1-243693379-A-G
• rs1973284
• NM_005465.7:c.172+2212T>C

Variant summary

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

The NM_005465.7(AKT3):​c.172+2212T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 147,058 control chromosomes in the GnomAD database, including 23,623 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 0.53 (23623 hom., cov: 22)
• Consequence: AKT3 NM_005465.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.400
• Publications: 0 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT3	NM_005465.7	c.172+2212T>C		intron_variant	Intron 3 of 13	ENST00000673466.1	NP_005456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT3	ENST00000673466.1	c.172+2212T>C		intron_variant	Intron 3 of 13		NM_005465.7	ENSP00000500582.1

Frequencies

GnomAD3 genomes AF: 0.526 AC: 77234 AN: 146950 Hom.: 23624 Cov.: 22

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.575

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

GnomAD4 genome AF: 0.525 AC: 77238 AN: 147058 Hom.: 23623 Cov.: 22 AF XY: 0.522 AC XY: 37271 AN XY: 71450

African (AFR) AF: 0.204 AC: 8173 AN: 40130

American (AMR) AF: 0.604 AC: 8812 AN: 14584

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2599 AN: 3422

East Asian (EAS) AF: 0.402 AC: 1975 AN: 4908

South Asian (SAS) AF: 0.476 AC: 2177 AN: 4576

European-Finnish (FIN) AF: 0.611 AC: 5889 AN: 9642

Middle Eastern (MID) AF: 0.629 AC: 180 AN: 286

European-Non Finnish (NFE) AF: 0.685 AC: 45633 AN: 66606

Other (OTH) AF: 0.573 AC: 1167 AN: 2036

Alfa AF: 0.571 Hom.: 3905

Bravo AF: 0.511

Asia WGS AF: 0.383 AC: 1327 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.3
DANN	Benign	0.81
PhyloP100		0.40
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: rs1973284; hg19: chr1-243856681;