chr12-57748221-TAA-T

Variant names:

• chr12-57748221-TAA-T
• rs59185470
• NM_000075.4:c.*302_*303delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000075.4(CDK4):​c.*302_*303delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 323,016 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (0 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*302_*303delTT		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*944_*945delAA		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.*302_*303delTT		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*944_*945delAA		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes AF: 0.0000656 AC: 9 AN: 137112 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000529

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000730

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000207

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000260

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000480

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00382 AC: 710 AN: 185868 Hom.: 0 AF XY: 0.00414 AC XY: 396 AN XY: 95564

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

African (AFR) AF: 0.00876 AC: 58 AN: 6618

American (AMR) AF: 0.00169 AC: 11 AN: 6520

Ashkenazi Jewish (ASJ) AF: 0.00156 AC: 11 AN: 7064

East Asian (EAS) AF: 0.00204 AC: 31 AN: 15210

South Asian (SAS) AF: 0.00741 AC: 163 AN: 21990

European-Finnish (FIN) AF: 0.00372 AC: 20 AN: 5374

Middle Eastern (MID) AF: 0.00491 AC: 4 AN: 814

European-Non Finnish (NFE) AF: 0.00345 AC: 383 AN: 110864

Other (OTH) AF: 0.00254 AC: 29 AN: 11414

⚠️ 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: 0.0000802 AC: 11 AN: 137148 Hom.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 9 AN XY: 66230

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

African (AFR) AF: 0.000106 AC: 4 AN: 37908

American (AMR) AF: 0.0000729 AC: 1 AN: 13716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3218

East Asian (EAS) AF: 0.000208 AC: 1 AN: 4806

South Asian (SAS) AF: 0.00 AC: 0 AN: 4322

European-Finnish (FIN) AF: 0.000260 AC: 2 AN: 7706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.0000480 AC: 3 AN: 62532

Other (OTH) AF: 0.00 AC: 0 AN: 1850

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000006), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
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: rs59185470; hg19: chr12-58142004;