rs3730597

Positions:

• chr12-68828045-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002392.6(MDM2):​c.524-726C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 152,258 control chromosomes in the GnomAD database, including 271 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.035 (271 hom., cov: 32)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.633

Genes affected

MDM2 (HGNC:6973): (MDM2 proto-oncogene) This gene encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. This gene is itself transcriptionally-regulated by p53. Overexpression or amplification of this locus is detected in a variety of different cancers. There is a pseudogene for this gene on chromosome 2. Alternative splicing results in a multitude of transcript variants, many of which may be expressed only in tumor cells. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDM2	NM_002392.6	c.524-726C>G		intron_variant		ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.524-726C>G		intron_variant		1	NM_002392.6	ENSP00000258149.6

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5260 AN: 152076 Hom.: 272 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.0795

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0307

GnomAD4 exome AF: 0.0156 AC: 1 AN: 64 Hom.: 0 AF XY: 0.0200 AC XY: 1 AN XY: 50

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0346 AC: 5260 AN: 152194 Hom.: 271 Cov.: 32 AF XY: 0.0423 AC XY: 3146 AN XY: 74410

Gnomad4 AFR AF: 0.00453

Gnomad4 AMR AF: 0.0705

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.0794

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0250 Hom.: 10

Bravo AF: 0.0300

Asia WGS AF: 0.143 AC: 502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.7
DANN	Benign	0.83

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: rs3730597; hg19: chr12-69221825;