12-57747747-CTTTT-CTTT

Variant names:

• chr12-57747747-CT-C
• rs146863045
• NM_000075.4:c.*777delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000075.4(CDK4):​c.*777delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 150,656 control chromosomes in the GnomAD database, including 78 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.028 (78 hom., cov: 31)
  • Exomes 𝑓: 0.19 (0 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.674
• Publications: 0 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.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0279 (4073/145856) while in subpopulation NFE AF = 0.0446 (2938/65924). AF 95% confidence interval is 0.0432. There are 78 homozygotes in GnomAd4. There are 1855 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4073 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*777delA		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*470delT		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.*777delA		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*470delT		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4075 AN: 145812 Hom.: 79 Cov.: 31

Gnomad AFR AF: 0.00870

Gnomad AMI AF: 0.00334

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00119

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.0445

Gnomad OTH AF: 0.0250

GnomAD4 exome AF: 0.190 AC: 911 AN: 4800 Hom.: 0 Cov.: 0 AF XY: 0.187 AC XY: 438 AN XY: 2338

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

African (AFR) AF: 0.162 AC: 12 AN: 74

American (AMR) AF: 0.188 AC: 72 AN: 384

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 49 AN: 234

East Asian (EAS) AF: 0.174 AC: 106 AN: 610

South Asian (SAS) AF: 0.174 AC: 40 AN: 230

European-Finnish (FIN) AF: 0.125 AC: 2 AN: 16

Middle Eastern (MID) AF: 0.115 AC: 3 AN: 26

European-Non Finnish (NFE) AF: 0.197 AC: 583 AN: 2966

Other (OTH) AF: 0.169 AC: 44 AN: 260

⚠️ 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: 0.0279 AC: 4073 AN: 145856 Hom.: 78 Cov.: 31 AF XY: 0.0261 AC XY: 1855 AN XY: 70974

African (AFR) AF: 0.00864 AC: 346 AN: 40068

American (AMR) AF: 0.0249 AC: 363 AN: 14596

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 34 AN: 3378

East Asian (EAS) AF: 0.00119 AC: 6 AN: 5040

South Asian (SAS) AF: 0.0135 AC: 62 AN: 4604

European-Finnish (FIN) AF: 0.0298 AC: 271 AN: 9090

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.0446 AC: 2938 AN: 65924

Other (OTH) AF: 0.0248 AC: 49 AN: 1976

Alfa AF: 0.00555 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism

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: rs146863045; hg19: chr12-58141530;