dbSNP rs1131690798: GSK3A:p.Gly49Val (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:

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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

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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