4-860924-T-C

Variant names:

• chr4-860924-T-C
• rs4690339
• NM_005255.4:c.3167-1202A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005255.4(GAK):​c.3167-1202A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,286 control chromosomes in the GnomAD database, including 2,413 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2413 hom., cov: 33)
• Consequence: GAK NM_005255.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.16
• Publications: 11 publications found

Genes affected

GAK (HGNC:4113): (cyclin G associated kinase) In all eukaryotes, the cell cycle is governed by cyclin-dependent protein kinases (CDKs), whose activities are regulated by cyclins and CDK inhibitors in a diverse array of mechanisms that involve the control of phosphorylation and dephosphorylation of Ser, Thr or Tyr residues. Cyclins are molecules that possess a consensus domain called the 'cyclin box.' In mammalian cells, 9 cyclin species have been identified, and they are referred to as cyclins A through I. Cyclin G is a direct transcriptional target of the p53 tumor suppressor gene product and thus functions downstream of p53. GAK is an association partner of cyclin G and CDK5. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAK	NM_005255.4	c.3167-1202A>G		intron_variant	Intron 23 of 27	ENST00000314167.9	NP_005246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAK	ENST00000314167.9	c.3167-1202A>G		intron_variant	Intron 23 of 27	1	NM_005255.4	ENSP00000314499.4

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26026 AN: 152168 Hom.: 2413 Cov.: 33

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.0767

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.171 AC: 26038 AN: 152286 Hom.: 2413 Cov.: 33 AF XY: 0.171 AC XY: 12722 AN XY: 74464

African (AFR) AF: 0.159 AC: 6589 AN: 41562

American (AMR) AF: 0.200 AC: 3065 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3472

East Asian (EAS) AF: 0.299 AC: 1547 AN: 5178

South Asian (SAS) AF: 0.315 AC: 1518 AN: 4824

European-Finnish (FIN) AF: 0.0767 AC: 814 AN: 10618

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10893 AN: 68016

Other (OTH) AF: 0.185 AC: 390 AN: 2112

Alfa AF: 0.169 Hom.: 9105

Bravo AF: 0.179

Asia WGS AF: 0.301 AC: 1050 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.30
DANN	Benign	0.39
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs4690339; hg19: chr4-854712;