NM_002392.6:c.358+537G>A

Variant names:

• chr12-68820911-G-A
• rs1201644
• NM_002392.6:c.358+537G>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.358+537G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 151,948 control chromosomes in the GnomAD database, including 23,115 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 0.53 (23115 hom., cov: 32)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 6 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 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.358+537G>A		intron	N/A	NP_002383.2
	MDM2	NM_001367990.1		c.340+537G>A		intron	N/A	NP_001354919.1
	MDM2	NM_001145337.3		c.340+537G>A		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.358+537G>A		intron	N/A	ENSP00000258149.6
	MDM2	ENST00000539479.6	TSL:1	c.340+537G>A		intron	N/A	ENSP00000444430.2
	MDM2	ENST00000350057.9	TSL:1	c.265+537G>A		intron	N/A	ENSP00000266624.9

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80387 AN: 151832 Hom.: 23072 Cov.: 32

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.481

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

GnomAD4 genome AF: 0.530 AC: 80495 AN: 151948 Hom.: 23115 Cov.: 32 AF XY: 0.520 AC XY: 38633 AN XY: 74260

African (AFR) AF: 0.757 AC: 31388 AN: 41456

American (AMR) AF: 0.359 AC: 5479 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1146 AN: 3468

East Asian (EAS) AF: 0.294 AC: 1521 AN: 5166

South Asian (SAS) AF: 0.311 AC: 1502 AN: 4826

European-Finnish (FIN) AF: 0.457 AC: 4807 AN: 10512

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 33021 AN: 67936

Other (OTH) AF: 0.481 AC: 1013 AN: 2108

Alfa AF: 0.503 Hom.: 4201

Bravo AF: 0.534

Asia WGS AF: 0.352 AC: 1224 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.17
PhyloP100		-1.2
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: rs1201644; hg19: chr12-69214691;