ENST00000316626.6:c.931T>A

Variant names:

• chr3-119866607-A-T
• rs2056186233
• ENST00000316626.6:c.931T>A

Variant summary

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

The ENST00000316626.6(GSK3B):​c.931T>A​(p.Phe311Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,452,686 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 13/20 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. F311V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GSK3B ENST00000316626.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.53
• Publications: 0 publications found

Genes affected

GSK3B (HGNC:4617): (glycogen synthase kinase 3 beta) The protein encoded by this gene is a serine-threonine kinase belonging to the glycogen synthase kinase subfamily. It is a negative regulator of glucose homeostasis and is involved in energy metabolism, inflammation, ER-stress, mitochondrial dysfunction, and apoptotic pathways. Defects in this gene have been associated with Parkinson disease and Alzheimer disease. [provided by RefSeq, Aug 2017]

GSK3B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000316626.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSK3B	NM_001146156.2	MANE Select	c.910-3002T>A		intron	N/A	NP_001139628.1	Q6FI27
	GSK3B	NM_002093.4		c.931T>A	p.Phe311Ile	missense	Exon 9 of 12	NP_002084.2
	GSK3B	NM_001354596.2		c.910-3002T>A		intron	N/A	NP_001341525.1	A0A3B3ITW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSK3B	ENST00000316626.6	TSL:1	c.931T>A	p.Phe311Ile	missense	Exon 9 of 12	ENSP00000324806.5	P49841-2
	GSK3B	ENST00000264235.13	TSL:1 MANE Select	c.910-3002T>A		intron	N/A	ENSP00000264235.9	P49841-1
	GSK3B	ENST00000899265.1		c.931T>A	p.Phe311Ile	missense	Exon 9 of 11	ENSP00000569324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1452686 Hom.: 0 Cov.: 27 AF XY: 0.0000208 AC XY: 15 AN XY: 722794

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

African (AFR) AF: 0.00 AC: 0 AN: 33136

American (AMR) AF: 0.00 AC: 0 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39392

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1105984

Other (OTH) AF: 0.00 AC: 0 AN: 60040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.95
Eigen	Benign	0.035
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.93	T
PhyloP100		5.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.41	T
Polyphen		0.32	B
Vest4		0.63
MutPred		0.39		Gain of glycosylation at T312 (P = 0.0353)
MVP		0.82
MPC		1.1
ClinPred		0.86	D
GERP RS		4.4
gMVP		0.27
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2056186233; hg19: chr3-119585454;