chr1-243505296-G-A

Variant names:

• chr1-243505296-G-A
• rs587776935
• NM_005465.7:c.1393C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000835228: Experimental studies have shown that this missense change affects AKT3 function (PMID:22729224, 23745724, 24705253).; SCV002318995: Published functional studies demonstrate that R465W caused increased activity compared to wild-type AKT3 (Alcantara et al., 2017);".

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT3 NM_005465.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:2
• Conservation: PhyloP100: 4.59
• Publications: 15 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000835228: Experimental studies have shown that this missense change affects AKT3 function (PMID: 22729224, 23745724, 24705253).; SCV002318995: Published functional studies demonstrate that R465W caused increased activity compared to wild-type AKT3 (Alcantara et al., 2017)
• PM2: Very rare variant in population databases, with high coverage
• 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 megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, microcephaly, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
• PP5: Variant 1-243505296-G-A is Pathogenic according to our data. Variant chr1-243505296-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT3	NM_005465.7	MANE Select	c.1393C>T	p.Arg465Trp	missense	Exon 14 of 14	NP_005456.1	Q9Y243-1
	AKT3	NM_001370074.1		c.1393C>T	p.Arg465Trp	missense	Exon 14 of 14	NP_001357003.1	Q9Y243-1
	AKT3	NM_001206729.2		c.1355-5510C>T		intron	N/A	NP_001193658.1	Q9Y243-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT3	ENST00000673466.1	MANE Select	c.1393C>T	p.Arg465Trp	missense	Exon 14 of 14	ENSP00000500582.1	Q9Y243-1
	AKT3	ENST00000263826.12	TSL:1	c.1393C>T	p.Arg465Trp	missense	Exon 14 of 14	ENSP00000263826.5	Q9Y243-1
	AKT3	ENST00000336199.9	TSL:1	c.1355-5510C>T		intron	N/A	ENSP00000336943.5	Q9Y243-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (8)
3	-	-	not provided (3)
1	-	-	AKT3-related disorder (1)
1	-	-	Capillary hemangioma;C0266464:Polymicrogyria;C0557874:Global developmental delay;C2243051:Macrocephaly (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	See cases (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.58		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
Mutation Taster		=22/78	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776935; hg19: chr1-243668598;