chr1-243554290-A-T

Variant names:

• chr1-243554290-A-T
• rs2220276
• NM_005465.7:c.949-1347T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005465.7(AKT3):​c.949-1347T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 152,026 control chromosomes in the GnomAD database, including 24,172 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.52 (24172 hom., cov: 32)
• Consequence: AKT3 NM_005465.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT3	NM_005465.7	MANE Select	c.949-1347T>A		intron	N/A	NP_005456.1
	AKT3	NM_001370074.1		c.949-1347T>A		intron	N/A	NP_001357003.1
	AKT3	NM_001206729.2		c.949-1347T>A		intron	N/A	NP_001193658.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT3	ENST00000673466.1	MANE Select	c.949-1347T>A		intron	N/A	ENSP00000500582.1
	AKT3	ENST00000263826.12	TSL:1	c.949-1347T>A		intron	N/A	ENSP00000263826.5
	AKT3	ENST00000336199.9	TSL:1	c.949-1347T>A		intron	N/A	ENSP00000336943.5

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79766 AN: 151908 Hom.: 24172 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.612

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.569

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

GnomAD4 genome AF: 0.525 AC: 79777 AN: 152026 Hom.: 24172 Cov.: 32 AF XY: 0.522 AC XY: 38808 AN XY: 74296

African (AFR) AF: 0.207 AC: 8595 AN: 41522

American (AMR) AF: 0.605 AC: 9224 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2507 AN: 3468

East Asian (EAS) AF: 0.486 AC: 2513 AN: 5166

South Asian (SAS) AF: 0.461 AC: 2224 AN: 4822

European-Finnish (FIN) AF: 0.619 AC: 6518 AN: 10536

Middle Eastern (MID) AF: 0.621 AC: 180 AN: 290

European-Non Finnish (NFE) AF: 0.679 AC: 46151 AN: 67944

Other (OTH) AF: 0.568 AC: 1202 AN: 2116

Alfa AF: 0.584 Hom.: 3496

Bravo AF: 0.509

Asia WGS AF: 0.420 AC: 1455 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.7
DANN	Benign	0.61
PhyloP100		0.071
Mutation Taster		=100/0	polymorphism (auto)

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: rs2220276; hg19: chr1-243717592;