rs397514605

Variant names:

• chr1-243613681-T-C
• rs397514605
• NM_005465.7:c.686A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_005465.7(AKT3):​c.686A>G​(p.Asn229Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N229H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT3 NM_005465.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 6.96

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Protein kinase (size 257) in uniprot entity AKT3_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_005465.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-243613682-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1518305.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the AKT3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.946 (above the threshold of 3.09). Trascript score misZ: 4.2291 (above the threshold of 3.09). GenCC associations: The gene is linked to microcephaly, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1.
• PP5: Variant 1-243613681-T-C is Pathogenic according to our data. Variant chr1-243613681-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 39815.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-243613681-T-C is described in UniProt as null. Variant chr1-243613681-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT3	NM_005465.7	c.686A>G	p.Asn229Ser	missense_variant	Exon 8 of 14	ENST00000673466.1	NP_005456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT3	ENST00000673466.1	c.686A>G	p.Asn229Ser	missense_variant	Exon 8 of 14		NM_005465.7	ENSP00000500582.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 Pathogenic:2 Other:1

Apr 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 229 of the AKT3 protein (p.Asn229Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (PMID: 22729224, 23745724, 28086757). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39815). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AKT3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AKT3 function (PMID: 25523067). For these reasons, this variant has been classified as Pathogenic. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1

Nov 01, 2015

Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Patient, a 3 year-old girl, showed severe developmental delay, hypotonia, seizure, and dysmorphic facial features. She had no meaningful words. Her last head circumference was 58 cm (+6.2SD). This mutation was confirmed de novo. The expression level of phosphorylated S6 ribosomal protein in her lymphoblastoid cell line was elevated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;D;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.49	N;N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.96	D;D;D;D
Vest4		0.81
MutPred		0.52		Gain of phosphorylation at N229 (P = 0.1548);Gain of phosphorylation at N229 (P = 0.1548);Gain of phosphorylation at N229 (P = 0.1548);Gain of phosphorylation at N229 (P = 0.1548);
MVP		0.58
MPC		1.7
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.59
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514605; hg19: chr1-243776983;