12-68808384-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002392.6(MDM2):c.-94A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,545,708 control chromosomes in the GnomAD database, including 115,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (10430 hom., cov: 32)
  • Exomes 𝑓: 0.38 (104902 hom.)
• Consequence: MDM2 NM_002392.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-68808384-A-G is Benign according to our data. Variant chr12-68808384-A-G is described in ClinVar as [Benign]. Clinvar id is 1164286.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM2	NM_002392.6	c.-94A>G		5_prime_UTR_variant	1/11	ENST00000258149.11
MDM2	NM_001145339.2	c.-94A>G		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM2	ENST00000258149.11	c.-94A>G		5_prime_UTR_variant	1/11	1	NM_002392.6

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55187 AN: 151902 Hom.: 10421 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.344

GnomAD4 exome AF: 0.382 AC: 532294 AN: 1393690 Hom.: 104902 Cov.: 22 AF XY: 0.377 AC XY: 262884 AN XY: 696746

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.419

Gnomad4 NFE exome AF: 0.408

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.363 AC: 55242 AN: 152018 Hom.: 10430 Cov.: 32 AF XY: 0.357 AC XY: 26548 AN XY: 74308

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.420

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.345

Alfa AF: 0.381 Hom.: 4443

Bravo AF: 0.350

Asia WGS AF: 0.281 AC: 976 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Accelerated tumor formation, susceptibility to Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	18
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs937283; hg19: chr12-69202164; COSMIC: COSV50700403; COSMIC: COSV50700403;