rs3730581

Positions:

• chr12-68825712-G-A

Variant summary

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

The NM_002392.6(MDM2):​c.523+1061G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 152,114 control chromosomes in the GnomAD database, including 8,888 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 0.31 (8888 hom., cov: 33)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15

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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM2	NM_002392.6	c.523+1061G>A		intron_variant		ENST00000258149.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM2	ENST00000258149.11	c.523+1061G>A		intron_variant		1	NM_002392.6

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47140 AN: 151996 Hom.: 8890 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.355

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.310 AC: 47132 AN: 152114 Hom.: 8888 Cov.: 33 AF XY: 0.320 AC XY: 23808 AN XY: 74354

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.512

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.353

Alfa AF: 0.351 Hom.: 10806

Bravo AF: 0.305

Asia WGS AF: 0.470 AC: 1635 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.60

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: rs3730581; hg19: chr12-69219492;