1-243637623-GA-TG

Variant names:

• chr1-243637623-GA-TG
• NM_005465.7:c.548_549delTCinsCA
• AKT3 p.Val183Ala

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP2

The NM_005465.7(AKT3):​c.548_549delTCinsCA​(p.Val183Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V183D) has been classified as Likely 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: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• 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: Labcorp Genetics (formerly Invitae), Illumina, 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: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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.

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.548_549delTCinsCA	p.Val183Ala	missense	N/A	NP_005456.1	Q9Y243-1
	AKT3	NM_001370074.1		c.548_549delTCinsCA	p.Val183Ala	missense	N/A	NP_001357003.1	Q9Y243-1
	AKT3	NM_001206729.2		c.548_549delTCinsCA	p.Val183Ala	missense	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.548_549delTCinsCA	p.Val183Ala	missense	N/A	ENSP00000500582.1	Q9Y243-1
	AKT3	ENST00000263826.12	TSL:1	c.548_549delTCinsCA	p.Val183Ala	missense	N/A	ENSP00000263826.5	Q9Y243-1
	AKT3	ENST00000336199.9	TSL:1	c.548_549delTCinsCA	p.Val183Ala	missense	N/A	ENSP00000336943.5	Q9Y243-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-243800925;