1-243637624-A-T

Variant names:

• chr1-243637624-A-T
• rs886041100
• NM_005465.7:c.548T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_005465.7(AKT3):​c.548T>A​(p.Val183Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V183A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT3 NM_005465.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.51
• Publications: 4 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: Likely_pathogenic. The variant received 6 ACMG points.

• 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-polydactyly-hydrocephalus syndrome 2, microcephaly, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• PP5: Variant 1-243637624-A-T is Pathogenic according to our data. Variant chr1-243637624-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 273671.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT3	NM_005465.7	c.548T>A	p.Val183Asp	missense_variant	Exon 6 of 14	ENST00000673466.1	NP_005456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT3	ENST00000673466.1	c.548T>A	p.Val183Asp	missense_variant	Exon 6 of 14		NM_005465.7	ENSP00000500582.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

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TIDEX, University of British Columbia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	.;.;D;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	-0.025	N;N;N;N
PhyloP100		7.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.042	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.85
MutPred		0.43		Loss of MoRF binding (P = 0.044);Loss of MoRF binding (P = 0.044);Loss of MoRF binding (P = 0.044);Loss of MoRF binding (P = 0.044);
MVP		0.85
MPC		2.9
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.92
gMVP		0.91
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs886041100; hg19: chr1-243800926;