12-57748206-C-T

Variant names:

• chr12-57748206-C-T
• rs775370483
• NM_000075.4:c.*319G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000075.4(CDK4):​c.*319G>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 0.000832 in 364,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (0 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.496
• Publications: 0 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BS2: High AC in GnomAd4 at 107 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.*319G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*916C>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	ENST00000257904.11	c.*319G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*916C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes AF: 0.000734 AC: 107 AN: 145692 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000273

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000109

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00151

GnomAD4 exome AF: 0.000898 AC: 196 AN: 218378 Hom.: 0 Cov.: 0 AF XY: 0.000887 AC XY: 100 AN XY: 112792

African (AFR) AF: 0.000133 AC: 1 AN: 7532

American (AMR) AF: 0.000976 AC: 7 AN: 7172

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 11 AN: 8236

East Asian (EAS) AF: 0.00 AC: 0 AN: 17120

South Asian (SAS) AF: 0.000302 AC: 8 AN: 26484

European-Finnish (FIN) AF: 0.000155 AC: 1 AN: 6432

Middle Eastern (MID) AF: 0.00106 AC: 1 AN: 940

European-Non Finnish (NFE) AF: 0.00120 AC: 158 AN: 131212

Other (OTH) AF: 0.000679 AC: 9 AN: 13250

GnomAD4 genome AF: 0.000734 AC: 107 AN: 145784 Hom.: 0 Cov.: 32 AF XY: 0.000679 AC XY: 48 AN XY: 70688

African (AFR) AF: 0.000282 AC: 11 AN: 39042

American (AMR) AF: 0.000273 AC: 4 AN: 14664

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4572

European-Finnish (FIN) AF: 0.000109 AC: 1 AN: 9158

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.00125 AC: 83 AN: 66640

Other (OTH) AF: 0.00149 AC: 3 AN: 2008

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000774

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		0.50
Mutation Taster		=99/1	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: rs775370483; hg19: chr12-58141989;