19-42234636-A-G

Position:

• chr19-42234636-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_019884.3(GSK3A):​c.709T>C​(p.Ser237Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GSK3A NM_019884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSK3A	NM_019884.3	c.709T>C	p.Ser237Pro	missense_variant	5/11	ENST00000222330.8	NP_063937.2
GSK3A	XR_001753673.2	n.846T>C		non_coding_transcript_exon_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSK3A	ENST00000222330.8	c.709T>C	p.Ser237Pro	missense_variant	5/11	1	NM_019884.3	ENSP00000222330.3
ENSG00000268643	ENST00000594664.1	c.448T>C	p.Ser150Pro	missense_variant	5/5	3		ENSP00000470087.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jan 04, 2024

The c.709T>C (p.S237P) alteration is located in exon 5 (coding exon 5) of the GSK3A gene. This alteration results from a T to C substitution at nucleotide position 709, causing the serine (S) at amino acid position 237 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	2.9	M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D;D;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.99	D;P;.
Vest4		0.74
MutPred		0.78		Loss of MoRF binding (P = 0.3002);.;.;
MVP		0.65
MPC		2.3
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42738788;