Genetic Variant NM_019884.3:c.146G>T (chr19-42242320-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019884.3(GSK3A):c.146G>T(p.Gly49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,283,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G49A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

GSK3A
NM_019884.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.67

Publications

0 publications found

Variant links:

Genes affected

GSK3A (HGNC:4616): (glycogen synthase kinase 3 alpha) This gene encodes a multifunctional Ser/Thr protein kinase that is implicated in the control of several regulatory proteins including glycogen synthase, and transcription factors, such as JUN. It also plays a role in the WNT and PI3K signaling pathways, as well as regulates the production of beta-amyloid peptides associated with Alzheimer's disease. [provided by RefSeq, Oct 2011]

GSK3A links:

ENSG00000268643 (HGNC:):

ENSG00000268643 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23224026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSK3A	NM_019884.3 link	c.146G>T	p.Gly49Val	missense_variant	Exon 1 of 11	ENST00000222330.8	NP_063937.2	P49840A0A024R0L5
GSK3A	XR_001753673.2 link	n.283G>T		non_coding_transcript_exon_variant	Exon 1 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSK3A	ENST00000222330.8 link	c.146G>T	p.Gly49Val	missense_variant	Exon 1 of 11	1	NM_019884.3	ENSP00000222330.3		P49840
ENSG00000268643	ENST00000594664.1 link	c.23-2178G>T		intron_variant	Intron 1 of 4	3		ENSP00000470087.1		M0QYV0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000156

AC:

AN:

1283808

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

632808

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25784

American (AMR)

AF:

0.00

AC:

AN:

20940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21804

East Asian (EAS)

AF:

0.00

AC:

AN:

27714

South Asian (SAS)

AF:

0.0000149

AC:

AN:

67120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3788

European-Non Finnish (NFE)

AF:

9.69e-7

AC:

AN:

1032244

Other (OTH)

AF:

0.00

AC:

AN:

52848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.79

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

2.7

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.48

REVEL

Benign

0.14

Sift

Benign

0.15

Sift4G

Uncertain

0.0080

Polyphen

0.62

Vest4

0.28

MutPred

0.34

Gain of sheet (P = 0.0101);

MVP

0.65

MPC

1.2

ClinPred

0.26

GERP RS

2.6

PromoterAI

-0.089

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.8

Varity_R

0.093

gMVP

0.60

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over