rs3730635

Variant names:

• chr12-68835343-A-G
• rs3730635
• NM_002392.6:c.685-486A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000258149.11(MDM2):​c.685-486A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0916 in 152,210 control chromosomes in the GnomAD database, including 945 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 0.092 (945 hom., cov: 32)
• Consequence: MDM2 ENST00000258149.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73
• Publications: 2 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000258149.11. 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.685-486A>G		intron	N/A	NP_002383.2
	MDM2	NM_001367990.1		c.667-486A>G		intron	N/A	NP_001354919.1
	MDM2	NM_001145337.3		c.667-486A>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.685-486A>G		intron	N/A	ENSP00000258149.6
	MDM2	ENST00000539479.6	TSL:1	c.667-486A>G		intron	N/A	ENSP00000444430.2
	MDM2	ENST00000350057.9	TSL:1	c.592-486A>G		intron	N/A	ENSP00000266624.9

Frequencies

GnomAD3 genomes AF: 0.0915 AC: 13924 AN: 152092 Hom.: 946 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0774

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0554

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0602

Gnomad OTH AF: 0.0865

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

GnomAD4 genome AF: 0.0916 AC: 13938 AN: 152210 Hom.: 945 Cov.: 32 AF XY: 0.0891 AC XY: 6630 AN XY: 74440

African (AFR) AF: 0.186 AC: 7709 AN: 41490

American (AMR) AF: 0.0772 AC: 1181 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3470

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5192

South Asian (SAS) AF: 0.0555 AC: 268 AN: 4830

European-Finnish (FIN) AF: 0.0236 AC: 250 AN: 10606

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0602 AC: 4093 AN: 68012

Other (OTH) AF: 0.0861 AC: 182 AN: 2114

Alfa AF: 0.0818 Hom.: 101

Bravo AF: 0.101

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.3
DANN	Benign	0.63
PhyloP100		1.7
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: rs3730635; hg19: chr12-69229123;