rs1196335

Variant names:

• chr12-68809744-T-A
• rs1196335
• NM_002392.6:c.99+452T>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.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
• 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)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MDM2	NM_002392.6	c.99+452T>A		intron_variant	Intron 2 of 10	ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.99+452T>A		intron_variant	Intron 2 of 10	1	NM_002392.6	ENSP00000258149.6

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

African (AFR) AF: 0.237 AC: 9839 AN: 41492

American (AMR) AF: 0.242 AC: 3697 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 915 AN: 3472

East Asian (EAS) AF: 0.279 AC: 1445 AN: 5172

South Asian (SAS) AF: 0.247 AC: 1191 AN: 4826

European-Finnish (FIN) AF: 0.442 AC: 4667 AN: 10550

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28799 AN: 67972

Other (OTH) AF: 0.326 AC: 689 AN: 2112

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
PhyloP100		-0.45
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: rs1196335; hg19: chr12-69203524;