12-57748004-C-T

Variant names:

• chr12-57748004-C-T
• rs113625101
• NM_000075.4:c.*521G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000075.4(CDK4):​c.*521G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0352 in 224,196 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (128 hom., cov: 32)
  • Exomes 𝑓: 0.039 (66 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.764

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-57748004-C-T is Benign according to our data. Variant chr12-57748004-C-T is described in ClinVar as [Benign]. Clinvar id is 309968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*521G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*714C>T		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	c.*521G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*714C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5114 AN: 152094 Hom.: 128 Cov.: 32

Gnomad AFR AF: 0.00799

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0449

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0494

Gnomad OTH AF: 0.0511

GnomAD4 exome AF: 0.0386 AC: 2777 AN: 71984 Hom.: 66 Cov.: 0 AF XY: 0.0387 AC XY: 1337 AN XY: 34592

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.0359

Gnomad4 ASJ exome AF: 0.0504

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.0232

Gnomad4 FIN exome AF: 0.0402

Gnomad4 NFE exome AF: 0.0473

Gnomad4 OTH exome AF: 0.0439

GnomAD4 genome AF: 0.0336 AC: 5114 AN: 152212 Hom.: 128 Cov.: 32 AF XY: 0.0329 AC XY: 2451 AN XY: 74432

Gnomad4 AFR AF: 0.00799

Gnomad4 AMR AF: 0.0380

Gnomad4 ASJ AF: 0.0449

Gnomad4 EAS AF: 0.000969

Gnomad4 SAS AF: 0.0259

Gnomad4 FIN AF: 0.0359

Gnomad4 NFE AF: 0.0494

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0383 Hom.: 15

Bravo AF: 0.0335

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs113625101; hg19: chr12-58141787;