14-96382228-CTTTTT-CTT

Variant names:

• chr14-96382228-CTTT-C
• rs34610576
• NM_016472.5:c.-1-7_-1-5delTTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_016472.5(GSKIP):​c.-1-7_-1-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,368,910 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: GSKIP NM_016472.5 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.35
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 14-96382228-CTTT-C is Benign according to our data. Variant chr14-96382228-CTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3034624.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016472.5. 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
	GSKIP	NM_016472.5	MANE Select	c.-1-7_-1-5delTTT		splice_region intron	N/A	NP_057556.2	Q9P0R6
	GSKIP	NM_001271904.1		c.-1-7_-1-5delTTT		splice_region intron	N/A	NP_001258833.1	Q9P0R6
	GSKIP	NM_001271905.2		c.-1-7_-1-5delTTT		splice_region intron	N/A	NP_001258834.1	Q9P0R6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSKIP	ENST00000555181.6	TSL:1 MANE Select	c.-1-18_-1-16delTTT		intron	N/A	ENSP00000450420.1	Q9P0R6
	GSKIP	ENST00000438650.5	TSL:2	c.-1-18_-1-16delTTT		intron	N/A	ENSP00000412315.1	Q9P0R6
	GSKIP	ENST00000554182.5	TSL:2	c.-1-18_-1-16delTTT		intron	N/A	ENSP00000451384.1	Q9P0R6

Frequencies

GnomAD3 genomes AF: 0.0000142 AC: 2 AN: 140626 Hom.: 0 Cov.: 32

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: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000156

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00263 AC: 271 AN: 102934 AF XY: 0.00246

Gnomad AFR exome AF: 0.00159

Gnomad AMR exome AF: 0.00413

Gnomad ASJ exome AF: 0.00333

Gnomad EAS exome AF: 0.00407

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00400

GnomAD4 exome AF: 0.000860 AC: 1056 AN: 1228284 Hom.: 0 AF XY: 0.000845 AC XY: 515 AN XY: 609178

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

African (AFR) AF: 0.000925 AC: 25 AN: 27016

American (AMR) AF: 0.00268 AC: 70 AN: 26108

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 30 AN: 20378

East Asian (EAS) AF: 0.000938 AC: 34 AN: 36256

South Asian (SAS) AF: 0.00166 AC: 112 AN: 67388

European-Finnish (FIN) AF: 0.00101 AC: 43 AN: 42638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4618

European-Non Finnish (NFE) AF: 0.000733 AC: 698 AN: 952696

Other (OTH) AF: 0.000860 AC: 44 AN: 51186

⚠️ 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 AF: 0.0000142 AC: 2 AN: 140626 Hom.: 0 Cov.: 32 AF XY: 0.0000147 AC XY: 1 AN XY: 68014

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

African (AFR) AF: 0.00 AC: 0 AN: 38462

American (AMR) AF: 0.00 AC: 0 AN: 14020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.00 AC: 0 AN: 4914

South Asian (SAS) AF: 0.00 AC: 0 AN: 4378

European-Finnish (FIN) AF: 0.000120 AC: 1 AN: 8346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000156 AC: 1 AN: 64102

Other (OTH) AF: 0.00 AC: 0 AN: 1920

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GSKIP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

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

Other links and lift over

dbSNP: rs34610576; hg19: chr14-96848565;