12-57747747-CTTTT-CT

Variant names:

• chr12-57747747-CTTT-C
• rs146863045
• NM_000075.4:c.*775_*777delAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000075.4(CDK4):​c.*775_*777delAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 151,336 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: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (0 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*775_*777delAAA		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*468_*470delTTT		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.*775_*777delAAA		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*468_*470delTTT		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes AF: 0.000157 AC: 23 AN: 146430 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000196

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00163 AC: 8 AN: 4906 Hom.: 0 AF XY: 0.00167 AC XY: 4 AN XY: 2400

⚠️ 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: 78

American (AMR) AF: 0.00254 AC: 1 AN: 394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 240

East Asian (EAS) AF: 0.00 AC: 0 AN: 632

South Asian (SAS) AF: 0.00 AC: 0 AN: 232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.00166 AC: 5 AN: 3020

Other (OTH) AF: 0.00746 AC: 2 AN: 268

⚠️ 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: 0.000157 AC: 23 AN: 146430 Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 11 AN XY: 71278

African (AFR) AF: 0.0000500 AC: 2 AN: 40038

American (AMR) AF: 0.000477 AC: 7 AN: 14660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.00 AC: 0 AN: 4624

European-Finnish (FIN) AF: 0.000108 AC: 1 AN: 9240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.000196 AC: 13 AN: 66240

Other (OTH) AF: 0.00 AC: 0 AN: 1972

Alfa AF: 0.000115 Hom.: 2

Bravo AF: 0.000125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;