chr12-57748221-T-TA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000075.4(CDK4):​c.*303dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 314,530 control chromosomes in the GnomAD database, including 101 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (101 hom., cov: 31)
  • Exomes 𝑓: 0.12 (0 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 = 0.0727 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3266 AN: 137020 Hom.: 100 Cov.: 31

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00414

Gnomad SAS AF: 0.00138

Gnomad FIN AF: 0.00701

Gnomad MID AF: 0.0106

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.0191

GnomAD4 exome AF: 0.117 AC: 20765 AN: 177474 Hom.: 0 Cov.: 0 AF XY: 0.116 AC XY: 10616 AN XY: 91596

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

African (AFR) AF: 0.135 AC: 865 AN: 6392

American (AMR) AF: 0.123 AC: 754 AN: 6118

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 848 AN: 6540

East Asian (EAS) AF: 0.107 AC: 1479 AN: 13844

South Asian (SAS) AF: 0.106 AC: 2316 AN: 21794

European-Finnish (FIN) AF: 0.115 AC: 616 AN: 5374

Middle Eastern (MID) AF: 0.117 AC: 89 AN: 760

European-Non Finnish (NFE) AF: 0.118 AC: 12457 AN: 105902

Other (OTH) AF: 0.125 AC: 1341 AN: 10750

⚠️ 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: 0.0239 AC: 3277 AN: 137056 Hom.: 101 Cov.: 31 AF XY: 0.0237 AC XY: 1568 AN XY: 66190

African (AFR) AF: 0.0750 AC: 2841 AN: 37896

American (AMR) AF: 0.0103 AC: 141 AN: 13706

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 40 AN: 3214

East Asian (EAS) AF: 0.00416 AC: 20 AN: 4810

South Asian (SAS) AF: 0.00139 AC: 6 AN: 4320

European-Finnish (FIN) AF: 0.00701 AC: 54 AN: 7704

Middle Eastern (MID) AF: 0.00775 AC: 2 AN: 258

European-Non Finnish (NFE) AF: 0.00221 AC: 138 AN: 62468

Other (OTH) AF: 0.0189 AC: 35 AN: 1848

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
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;