chr12-57748155-A-C

Variant names:

• chr12-57748155-A-C
• rs3473
• NM_000075.4:c.*370T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000075.4(CDK4):​c.*370T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 350,076 control chromosomes in the GnomAD database, including 326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (279 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (47 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.12
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-57748155-A-C is Benign according to our data. Variant chr12-57748155-A-C is described in ClinVar as Benign. ClinVar VariationId is 309972.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 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.*370T>G		3_prime_UTR	Exon 8 of 8	NP_000066.1	P11802-1
	TSPAN31	NM_005981.5	MANE Select	c.*865A>C		3_prime_UTR	Exon 6 of 6	NP_005972.1	Q12999
	TSPAN31	NM_001330169.2		c.*865A>C		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.*370T>G		3_prime_UTR	Exon 8 of 8	ENSP00000257904.5	P11802-1
	TSPAN31	ENST00000257910.8	TSL:1 MANE Select	c.*865A>C		3_prime_UTR	Exon 6 of 6	ENSP00000257910.3	Q12999
	TSPAN31	ENST00000547992.5	TSL:1	c.*865A>C		3_prime_UTR	Exon 4 of 4	ENSP00000448209.1	F8VS78

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4959 AN: 152120 Hom.: 277 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00470 AC: 929 AN: 197838 Hom.: 47 Cov.: 0 AF XY: 0.00386 AC XY: 390 AN XY: 100940

African (AFR) AF: 0.109 AC: 734 AN: 6726

American (AMR) AF: 0.00795 AC: 53 AN: 6668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7648

East Asian (EAS) AF: 0.00 AC: 0 AN: 16234

South Asian (SAS) AF: 0.000276 AC: 6 AN: 21700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5114

Middle Eastern (MID) AF: 0.00231 AC: 2 AN: 866

European-Non Finnish (NFE) AF: 0.000266 AC: 32 AN: 120482

Other (OTH) AF: 0.00823 AC: 102 AN: 12400

GnomAD4 genome AF: 0.0326 AC: 4970 AN: 152238 Hom.: 279 Cov.: 32 AF XY: 0.0314 AC XY: 2334 AN XY: 74438

African (AFR) AF: 0.114 AC: 4746 AN: 41500

American (AMR) AF: 0.0114 AC: 175 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68022

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0181 Hom.: 36

Bravo AF: 0.0373

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs3473; hg19: chr12-58141938;