rs1196335

chr12-68809744-T-A

Variant summary

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

The NM_002392.6(MDM2):c.99+452T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 152,098 control chromosomes in the GnomAD database, including 9,533 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 0.34 (9533 hom., cov: 32)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.446

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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM2	NM_002392.6	c.99+452T>A		intron_variant		ENST00000258149.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM2	ENST00000258149.11	c.99+452T>A		intron_variant		1	NM_002392.6

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51760 AN: 151980 Hom.: 9529 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.325

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

GnomAD4 genome AF: 0.341 AC: 51796 AN: 152098 Hom.: 9533 Cov.: 32 AF XY: 0.337 AC XY: 25077 AN XY: 74352

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.424

Gnomad4 OTH AF: 0.326

Alfa AF: 0.391 Hom.: 1552

Bravo AF: 0.323

Asia WGS AF: 0.282 AC: 976 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	8.0
Dann	Benign	0.78

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: rs1196335; hg19: chr12-69203524;