12-57748221-TA-T

Variant names:

• chr12-57748221-TA-T
• rs59185470
• NM_000075.4:c.*303delT

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*303delT		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*945delA		3_prime_UTR_variant	Exon 6 of 6	ENST00000257910.8	NP_005972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.*303delT		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*945delA		3_prime_UTR_variant	Exon 6 of 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

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

African (AFR) AF: 0.276 AC: 1708 AN: 6180

American (AMR) AF: 0.267 AC: 1510 AN: 5666

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 1349 AN: 5920

East Asian (EAS) AF: 0.244 AC: 2959 AN: 12132

South Asian (SAS) AF: 0.257 AC: 5419 AN: 21108

European-Finnish (FIN) AF: 0.209 AC: 1088 AN: 5218

Middle Eastern (MID) AF: 0.231 AC: 163 AN: 706

European-Non Finnish (NFE) AF: 0.236 AC: 23323 AN: 98624

Other (OTH) AF: 0.239 AC: 2389 AN: 10006

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.152 AC: 5773 AN: 37872

American (AMR) AF: 0.0213 AC: 291 AN: 13684

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 8 AN: 3214

East Asian (EAS) AF: 0.00583 AC: 28 AN: 4802

South Asian (SAS) AF: 0.0720 AC: 311 AN: 4322

European-Finnish (FIN) AF: 0.0171 AC: 131 AN: 7660

Middle Eastern (MID) AF: 0.0155 AC: 4 AN: 258

European-Non Finnish (NFE) AF: 0.00550 AC: 343 AN: 62342

Other (OTH) AF: 0.0390 AC: 72 AN: 1846

Alfa AF: 0.00139 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cutaneous Malignant Melanoma, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
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: rs59185470; hg19: chr12-58142004;