NM_001146156.2:c.-1001T>C

Variant names:

• chr3-120094435-A-G
• rs334558
• NM_001146156.2:c.-1001T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001146156.2(GSK3B):​c.-1001T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 296,038 control chromosomes in the GnomAD database, including 38,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (23682 hom., cov: 33)
  • Exomes 𝑓: 0.44 (14698 hom.)
• Consequence: GSK3B NM_001146156.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83
• Publications: 148 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-120094435-A-G is Benign according to our data. Variant chr3-120094435-A-G is described in ClinVar as Benign. ClinVar VariationId is 1258187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146156.2. 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.-1001T>C		5_prime_UTR	Exon 1 of 11	NP_001139628.1	Q6FI27
	GSK3B	NM_002093.4		c.-1001T>C		5_prime_UTR	Exon 1 of 12	NP_002084.2
	GSK3B	NM_001354596.2		c.-1001T>C		5_prime_UTR	Exon 1 of 10	NP_001341525.1	A0A3B3ITW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSK3B	ENST00000264235.13	TSL:1 MANE Select	c.-1001T>C		5_prime_UTR	Exon 1 of 11	ENSP00000264235.9	P49841-1
	GSK3B	ENST00000899266.1		c.-1001T>C		5_prime_UTR	Exon 1 of 11	ENSP00000569325.1
	GSK3B	ENST00000899265.1		c.-1001T>C		5_prime_UTR	Exon 1 of 11	ENSP00000569324.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77646 AN: 151950 Hom.: 23628 Cov.: 33

Gnomad AFR AF: 0.854

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.438 AC: 63023 AN: 143972 Hom.: 14698 Cov.: 0 AF XY: 0.444 AC XY: 35308 AN XY: 79534

African (AFR) AF: 0.864 AC: 3115 AN: 3604

American (AMR) AF: 0.355 AC: 990 AN: 2786

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 2207 AN: 5522

East Asian (EAS) AF: 0.635 AC: 7633 AN: 12012

South Asian (SAS) AF: 0.564 AC: 9206 AN: 16314

European-Finnish (FIN) AF: 0.397 AC: 1473 AN: 3706

Middle Eastern (MID) AF: 0.459 AC: 329 AN: 716

European-Non Finnish (NFE) AF: 0.377 AC: 34085 AN: 90294

Other (OTH) AF: 0.442 AC: 3985 AN: 9018

GnomAD4 genome AF: 0.511 AC: 77762 AN: 152066 Hom.: 23682 Cov.: 33 AF XY: 0.510 AC XY: 37939 AN XY: 74348

African (AFR) AF: 0.855 AC: 35481 AN: 41522

American (AMR) AF: 0.378 AC: 5781 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1398 AN: 3472

East Asian (EAS) AF: 0.619 AC: 3189 AN: 5154

South Asian (SAS) AF: 0.557 AC: 2684 AN: 4818

European-Finnish (FIN) AF: 0.369 AC: 3897 AN: 10574

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23933 AN: 67928

Other (OTH) AF: 0.491 AC: 1036 AN: 2112

Alfa AF: 0.391 Hom.: 17759

Bravo AF: 0.522

Asia WGS AF: 0.594 AC: 2055 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.76
PhyloP100		1.8
PromoterAI		-0.081	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs334558; hg19: chr3-119813282;