rs3730597

Variant names:

• chr12-68828045-C-G
• rs3730597
• NM_002392.6:c.524-726C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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)

ENSG00000256325 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

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.524-726C>G		intron	N/A	NP_002383.2
	MDM2	NM_001367990.1		c.506-726C>G		intron	N/A	NP_001354919.1
	MDM2	NM_001145337.3		c.506-726C>G		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.524-726C>G		intron	N/A	ENSP00000258149.6
	MDM2	ENST00000539479.6	TSL:1	c.506-726C>G		intron	N/A	ENSP00000444430.2
	MDM2	ENST00000350057.9	TSL:1	c.431-726C>G		intron	N/A	ENSP00000266624.9

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0192 AC: 1 AN: 52

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.00453 AC: 188 AN: 41538

American (AMR) AF: 0.0705 AC: 1078 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.187 AC: 965 AN: 5172

South Asian (SAS) AF: 0.0794 AC: 383 AN: 4826

European-Finnish (FIN) AF: 0.134 AC: 1422 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0165 AC: 1119 AN: 68012

Other (OTH) AF: 0.0303 AC: 64 AN: 2110

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.7
DANN	Benign	0.83
PhyloP100		-0.63
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: rs3730597; hg19: chr12-69221825;