chr12-57748004-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000075.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK4	NM_000075.4	MANE Select	c.*521G>A		3_prime_UTR	Exon 8 of 8	NP_000066.1	P11802-1
	TSPAN31	NM_005981.5	MANE Select	c.*714C>T		3_prime_UTR	Exon 6 of 6	NP_005972.1	Q12999
	TSPAN31	NM_001330169.2		c.*714C>T		3_prime_UTR	Exon 6 of 6	NP_001317098.1	B4DFJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK4	ENST00000257904.11	TSL:1 MANE Select	c.*521G>A		3_prime_UTR	Exon 8 of 8	ENSP00000257904.5	P11802-1
	TSPAN31	ENST00000257910.8	TSL:1 MANE Select	c.*714C>T		3_prime_UTR	Exon 6 of 6	ENSP00000257910.3	Q12999
	TSPAN31	ENST00000547992.5	TSL:1	c.*714C>T		3_prime_UTR	Exon 4 of 4	ENSP00000448209.1	F8VS78

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

African (AFR) AF: 0.0124 AC: 31 AN: 2502

American (AMR) AF: 0.0359 AC: 148 AN: 4128

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 184 AN: 3654

East Asian (EAS) AF: 0.000109 AC: 1 AN: 9152

South Asian (SAS) AF: 0.0232 AC: 70 AN: 3018

European-Finnish (FIN) AF: 0.0402 AC: 16 AN: 398

Middle Eastern (MID) AF: 0.102 AC: 38 AN: 372

European-Non Finnish (NFE) AF: 0.0473 AC: 2056 AN: 43448

Other (OTH) AF: 0.0439 AC: 233 AN: 5312

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

African (AFR) AF: 0.00799 AC: 332 AN: 41540

American (AMR) AF: 0.0380 AC: 582 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0449 AC: 156 AN: 3472

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5162

South Asian (SAS) AF: 0.0259 AC: 125 AN: 4828

European-Finnish (FIN) AF: 0.0359 AC: 380 AN: 10590

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0494 AC: 3362 AN: 67996

Other (OTH) AF: 0.0511 AC: 108 AN: 2114

Alfa AF: 0.0383 Hom.: 15

Bravo AF: 0.0335

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.95
PhyloP100		-0.76
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: rs113625101; hg19: chr12-58141787;