rs3730635

Variant names:

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

Variant summary

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

The NM_002392.6(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 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6	c.685-486A>G		intron_variant	Intron 8 of 10	ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.685-486A>G		intron_variant	Intron 8 of 10	1	NM_002392.6	ENSP00000258149.6

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

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.0772

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.0555

Gnomad4 FIN AF: 0.0236

Gnomad4 NFE AF: 0.0602

Gnomad4 OTH AF: 0.0861

Alfa AF: 0.0779 Hom.: 88

Bravo AF: 0.101

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.3
DANN	Benign	0.63

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: rs3730635; hg19: chr12-69229123;