rs397514605

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV005834083: Experimental studies have shown that this missense change affects AKT3 function (PMID:25523067).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N229I) has been classified as Pathogenic. The gene AKT3 is included in the ClinGen Criteria Specification Registry.

• 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
• Publications: 6 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

Specifications for AKT3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005834083: Experimental studies have shown that this missense change affects AKT3 function (PMID: 25523067).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-243613681-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4527055.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 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 1-243613681-T-C is Pathogenic according to our data. Variant chr1-243613681-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 39815.Status of the report is criteria_provided_single_submitter, 1 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.686A>G	p.Asn229Ser	missense	Exon 8 of 14	NP_005456.1	Q9Y243-1
	AKT3	NM_001370074.1		c.686A>G	p.Asn229Ser	missense	Exon 8 of 14	NP_001357003.1	Q9Y243-1
	AKT3	NM_001206729.2		c.686A>G	p.Asn229Ser	missense	Exon 8 of 14	NP_001193658.1	Q9Y243-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT3	ENST00000673466.1	MANE Select	c.686A>G	p.Asn229Ser	missense	Exon 8 of 14	ENSP00000500582.1	Q9Y243-1
	AKT3	ENST00000263826.12	TSL:1	c.686A>G	p.Asn229Ser	missense	Exon 8 of 14	ENSP00000263826.5	Q9Y243-1
	AKT3	ENST00000336199.9	TSL:1	c.686A>G	p.Asn229Ser	missense	Exon 7 of 14	ENSP00000336943.5	Q9Y243-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (3)
1	-	-	Megalencephaly-capillary malformation-polymicrogyria syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.49	N
PhyloP100		7.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		0.96	D
Vest4		0.81
MutPred		0.52		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
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs397514605; hg19: chr1-243776983;