rs587776935

Positions:

• chr1-243505296-G-A
• chr1-243505296-G-C
• chr1-243505296-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_005465.7(AKT3):​c.1393C>T​(p.Arg465Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT3 NM_005465.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:2
• Conservation: PhyloP100: 4.59

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a region_of_interest Disordered (size 21) in uniprot entity AKT3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005465.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AKT3. . Gene score misZ 3.946 (greater than the threshold 3.09). Trascript score misZ 4.2291 (greater than threshold 3.09). GenCC has associacion of gene with 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 1-243505296-G-A is Pathogenic according to our data. Variant chr1-243505296-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-243505296-G-A is described in UniProt as null. Variant chr1-243505296-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-243505296-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT3	NM_005465.7	c.1393C>T	p.Arg465Trp	missense_variant	14/14	ENST00000673466.1	NP_005456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT3	ENST00000673466.1	c.1393C>T	p.Arg465Trp	missense_variant	14/14		NM_005465.7	ENSP00000500582.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 Pathogenic:6 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AKT3 function (PMID: 22729224, 23745724, 24705253). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 39814). This missense change has been observed in individual(s) with overlapping features of megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) (PMID: 22729224, 23745724). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 465 of the AKT3 protein (p.Arg465Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (PMID: 23745724, 22729224, PS2, PS4_M). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2. Missense changes are a common disease-causing mechanism (PP2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MPPH) (MIM#615937) (GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated kinase C-terminal domain (DECIPHER, Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least five patients, including proven de novo events, and has been classified as pathogenic by diagnostic laboratories in ClinVar (DECIPHER; PMID: 22729224, 29286531, 33176815). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jan 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	May 16, 2023	This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Pathogenic (II):PP3;PP2;PM2;PS4;PS2 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2022	Published functional studies demonstrate that R465W caused increased activity compared to wild-type AKT3 (Alcantara et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28475857, 28973083, 29286531, 32446860, 33942996, 33176815, 31785789, 22729224, 23592320, 25140959, 28969385) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2017

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 18, 2019

ACMG classification criteria: PS2, PS4, PM2, PP2, PP3 -

Capillary hemangioma;C0266464:Polymicrogyria;C0557874:Global developmental delay;C2243051:Macrocephaly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 06, 2014

- -

AKT3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2022

The AKT3 c.1393C>T variant is predicted to result in the amino acid substitution p.Arg465Trp. This variant has been reported de novo in multiple individuals with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (Rivière et al. 2012. PMID: 22729224, Table 1 Alacantara et al. 2017. PMID: 28969385, eTable 3 Meng et al. 2017. PMID: 28973083, S Table 1 Tumiene et al. 2018. PMID: 29286531, Table 1 Lin et al. 2020 PMID: 33176815, Results section 3.3.2 Moirangthem et al 2021 PMID: 33942996.) This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.58		Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);
MVP		0.78
MPC		2.5
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.75
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs587776935; hg19: chr1-243668598; COSMIC: COSV55616839;