14-96382329-A-T

Position:

chr14-96382329-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016472.5(GSKIP):c.82A>T(p.Thr28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GSKIP
NM_016472.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.31

Variant links:

Genes affected

GSKIP (HGNC:20343): (GSK3B interacting protein) This gene encodes a protein that is involved as a negative regulator of GSK3-beta in the Wnt signaling pathway. The encoded protein may play a role in the retinoic acid signaling pathway by regulating the functional interactions between GSK3-beta, beta-catenin and cyclin D1, and it regulates the beta-catenin/N-cadherin pool. The encoded protein contains a GSK3-beta interacting domain (GID) in its C-terminus, which is similar to the GID of Axin. The protein also contains an evolutionarily conserved RII-binding domain, which facilitates binding with protein kinase-A and GSK3-beta, enabling its role as an A-kinase anchoring protein. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2012]

GSKIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050076574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSKIP	NM_016472.5 linkuse as main transcript	c.82A>T	p.Thr28Ser	missense_variant	3/4	ENST00000555181.6	NP_057556.2	Q9P0R6A0A024R6P6
GSKIP	NM_001271904.1 linkuse as main transcript	c.82A>T	p.Thr28Ser	missense_variant	3/4		NP_001258833.1	Q9P0R6A0A024R6P6
GSKIP	NM_001271905.2 linkuse as main transcript	c.82A>T	p.Thr28Ser	missense_variant	3/4		NP_001258834.1	Q9P0R6A0A024R6P6
GSKIP	NM_001271906.2 linkuse as main transcript	c.82A>T	p.Thr28Ser	missense_variant	2/3		NP_001258835.1	Q9P0R6A0A024R6P6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSKIP	ENST00000555181.6 linkuse as main transcript	c.82A>T	p.Thr28Ser	missense_variant	3/4	1	NM_016472.5	ENSP00000450420.1		Q9P0R6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251464

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461552

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 22, 2022

DNA sequence analysis of the GSKIP gene demonstrated a sequence change, c.82A>T, in exon 3 that results in an amino acid change, p.Thr28Ser. This sequence change does not appear to have been previously described in individuals with GSKIP-related disorders. This sequence change has been described in the gnomAD database with a global population frequency of 0.001% (dbSNP rs1294989957). The p.Thr28Ser change affects a poorly conserved amino acid residue located in a domain of the GSKIP protein that is known to be functional. The p.Thr28Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr28Ser change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.028

T;T;.;T;T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.56

T;.;T;.;.;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.050

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

L;L;.;L;L;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.20

N;N;N;N;N;N

REVEL

Benign

0.038

Sift

Benign

0.53

T;T;T;T;T;T

Sift4G

Benign

0.069

T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;B;.

Vest4

0.22

MutPred

0.25

Gain of catalytic residue at M33 (P = 0.0031);Gain of catalytic residue at M33 (P = 0.0031);Gain of catalytic residue at M33 (P = 0.0031);Gain of catalytic residue at M33 (P = 0.0031);Gain of catalytic residue at M33 (P = 0.0031);Gain of catalytic residue at M33 (P = 0.0031);

MVP

0.13

MPC

0.37

ClinPred

0.022

GERP RS

-0.80

Varity_R

0.026

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over