chr14-96382228-C-CTTTT

Variant names:

• chr14-96382228-C-CTTTT
• rs34610576
• NM_016472.5:c.-1-8_-1-5dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016472.5(GSKIP):​c.-1-8_-1-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000404 in 1,236,154 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: GSKIP NM_016472.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.-1-8_-1-5dupTTTT		splice_region intron	N/A	NP_057556.2	Q9P0R6
	GSKIP	NM_001271904.1		c.-1-8_-1-5dupTTTT		splice_region intron	N/A	NP_001258833.1	Q9P0R6
	GSKIP	NM_001271905.2		c.-1-8_-1-5dupTTTT		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.-1-19_-1-18insTTTT		intron	N/A	ENSP00000450420.1	Q9P0R6
	GSKIP	ENST00000438650.5	TSL:2	c.-1-19_-1-18insTTTT		intron	N/A	ENSP00000412315.1	Q9P0R6
	GSKIP	ENST00000554182.5	TSL:2	c.-1-19_-1-18insTTTT		intron	N/A	ENSP00000451384.1	Q9P0R6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000404 AC: 5 AN: 1236154 Hom.: 0 Cov.: 0 AF XY: 0.00000326 AC XY: 2 AN XY: 612990

⚠️ 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: 27170

American (AMR) AF: 0.00 AC: 0 AN: 26284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20524

East Asian (EAS) AF: 0.00 AC: 0 AN: 36432

South Asian (SAS) AF: 0.0000294 AC: 2 AN: 67972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4640

European-Non Finnish (NFE) AF: 0.00000313 AC: 3 AN: 958794

Other (OTH) AF: 0.00 AC: 0 AN: 51502

⚠️ 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
PhyloP100		1.3

Splicing

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

Other links and lift over

dbSNP: rs34610576; hg19: chr14-96848565;