chr12-68825712-G-A

Variant names:

• chr12-68825712-G-A
• rs3730581
• NM_002392.6:c.523+1061G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

MDM2 Gene-Disease associations (from GenCC):

• Li-Fraumeni syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lessel-kubisch syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002392.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	NM_002392.6	MANE Select	c.523+1061G>A		intron	N/A	NP_002383.2
	MDM2	NM_001367990.1		c.505+1061G>A		intron	N/A	NP_001354919.1
	MDM2	NM_001145337.3		c.505+1061G>A		intron	N/A	NP_001138809.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM2	ENST00000258149.11	TSL:1 MANE Select	c.523+1061G>A		intron	N/A	ENSP00000258149.6
	MDM2	ENST00000539479.6	TSL:1	c.505+1061G>A		intron	N/A	ENSP00000444430.2
	MDM2	ENST00000350057.9	TSL:1	c.430+1061G>A		intron	N/A	ENSP00000266624.9

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

African (AFR) AF: 0.100 AC: 4166 AN: 41458

American (AMR) AF: 0.477 AC: 7297 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1771 AN: 3472

East Asian (EAS) AF: 0.512 AC: 2647 AN: 5172

South Asian (SAS) AF: 0.523 AC: 2524 AN: 4828

European-Finnish (FIN) AF: 0.411 AC: 4352 AN: 10590

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23248 AN: 67984

Other (OTH) AF: 0.353 AC: 745 AN: 2112

Alfa AF: 0.344 Hom.: 15241

Bravo AF: 0.305

Asia WGS AF: 0.470 AC: 1635 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.60
PhyloP100		-1.1
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: rs3730581; hg19: chr12-69219492;