19-42242342-C-T

Position:

• chr19-42242342-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019884.3(GSK3A):​c.124G>A​(p.Gly42Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000236 in 1,271,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: GSK3A NM_019884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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]

ENSG00000268643 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36042583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSK3A	NM_019884.3	c.124G>A	p.Gly42Ser	missense_variant	1/11	ENST00000222330.8	NP_063937.2
GSK3A	XR_001753673.2	n.261G>A		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSK3A	ENST00000222330.8	c.124G>A	p.Gly42Ser	missense_variant	1/11	1	NM_019884.3	ENSP00000222330.3
ENSG00000268643	ENST00000594664.1	c.23-2200G>A		intron_variant		3		ENSP00000470087.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000236 AC: 3 AN: 1271614 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 626264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000987

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.75e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2021

The c.124G>A (p.G42S) alteration is located in exon 1 (coding exon 1) of the GSK3A gene. This alteration results from a G to A substitution at nucleotide position 124, causing the glycine (G) at amino acid position 42 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.42	N
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.34	N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.35
Sift	Benign	0.63	T
Sift4G	Benign	0.44	T
Polyphen		0.46	P
Vest4		0.33
MutPred		0.23		Gain of phosphorylation at G42 (P = 0.0024);
MVP		0.84
MPC		0.99
ClinPred		0.39	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.10
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1256218535; hg19: chr19-42746494;