chr1-243843133-T-C

Variant names:

• chr1-243843133-T-C
• rs1553462330
• NM_005465.7:c.38A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005465.7(AKT3):​c.38A>G​(p.Gln13Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT3 NM_005465.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51
• Publications: 0 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: Uncertain_significance. The variant received 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT3	NM_005465.7	c.38A>G	p.Gln13Arg	missense_variant	Exon 2 of 14	ENST00000673466.1	NP_005456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT3	ENST00000673466.1	c.38A>G	p.Gln13Arg	missense_variant	Exon 2 of 14		NM_005465.7	ENSP00000500582.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 18, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	.;.;D;D;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.6	L;L;L;L;.
PhyloP100		5.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.42	B;B;B;B;.
Vest4		0.78
MutPred		0.60		Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);
MVP		0.91
MPC		1.3
ClinPred		0.44	T
GERP RS		5.7
PromoterAI		0.11	Neutral
Varity_R		0.58
gMVP		0.77
Mutation Taster		=46/54	disease causing

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: rs1553462330; hg19: chr1-244006435;