12-57748221-TA-T

Position:

• chr12-57748221-TA-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000075.4(CDK4):​c.*303delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 302,392 control chromosomes in the GnomAD database, including 424 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.051 (418 hom., cov: 31)
  • Exomes 𝑓: 0.24 (6 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.557

Genes affected

CDK4 (HGNC:1773): (cyclin dependent kinase 4) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

TSPAN31 (HGNC:10539): (tetraspanin 31) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is thought to be involved in growth-related cellular processes. This gene is associated with tumorigenesis and osteosarcoma. [provided by RefSeq, Jul 2008]

TSPAN31 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*303delT		3_prime_UTR_variant	8/8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*945delA		3_prime_UTR_variant	6/6	ENST00000257910.8	NP_005972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904	c.*303delT		3_prime_UTR_variant	8/8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*945delA		3_prime_UTR_variant	6/6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes AF: 0.0507 AC: 6929 AN: 136798 Hom.: 413 Cov.: 31

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00249

Gnomad EAS AF: 0.00581

Gnomad SAS AF: 0.0711

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0141

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.0316

GnomAD4 exome AF: 0.241 AC: 39908 AN: 165560 Hom.: 6 Cov.: 0 AF XY: 0.240 AC XY: 20617 AN XY: 85804

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.209

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.239

GnomAD4 genome AF: 0.0509 AC: 6961 AN: 136832 Hom.: 418 Cov.: 31 AF XY: 0.0516 AC XY: 3408 AN XY: 66030

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.00249

Gnomad4 EAS AF: 0.00583

Gnomad4 SAS AF: 0.0720

Gnomad4 FIN AF: 0.0171

Gnomad4 NFE AF: 0.00550

Gnomad4 OTH AF: 0.0390

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cutaneous Malignant Melanoma, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs59185470; hg19: chr12-58142004;