14-96382376-T-A

Position:

• chr14-96382376-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016472.5(GSKIP):​c.129T>A​(p.Asp43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GSKIP NM_016472.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.549

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14959285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSKIP	NM_016472.5	c.129T>A	p.Asp43Glu	missense_variant	3/4	ENST00000555181.6	NP_057556.2
GSKIP	NM_001271904.1	c.129T>A	p.Asp43Glu	missense_variant	3/4		NP_001258833.1
GSKIP	NM_001271905.2	c.129T>A	p.Asp43Glu	missense_variant	3/4		NP_001258834.1
GSKIP	NM_001271906.2	c.129T>A	p.Asp43Glu	missense_variant	2/3		NP_001258835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSKIP	ENST00000555181.6	c.129T>A	p.Asp43Glu	missense_variant	3/4	1	NM_016472.5	ENSP00000450420	P1

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 23, 2024

The c.129T>A (p.D43E) alteration is located in exon 2 (coding exon 1) of the GSKIP gene. This alteration results from a T to A substitution at nucleotide position 129, causing the aspartic acid (D) at amino acid position 43 to be replaced by a glutamic acid (E). 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	0.97
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	8.5
DANN	Benign	0.95
DEOGEN2	Benign	0.044	T;T;.;T;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.71	T;.;T;.;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.5	L;L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.050	N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.93	T;T;T;T;T;T
Sift4G	Benign	0.39	T;T;D;T;T;T
Polyphen		0.99	D;D;.;D;D;.
Vest4		0.77
MutPred		0.50		Gain of catalytic residue at V48 (P = 0);Gain of catalytic residue at V48 (P = 0);Gain of catalytic residue at V48 (P = 0);Gain of catalytic residue at V48 (P = 0);Gain of catalytic residue at V48 (P = 0);Gain of catalytic residue at V48 (P = 0);
MVP		0.59
MPC		0.93
ClinPred		0.36	T
GERP RS		-6.4
Varity_R		0.083
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-96848713;