rs937283

Variant names:

• chr12-68808384-A-G
• rs937283
• NM_002392.6:c.-94A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29
• Publications: 59 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 -20 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 VariationId is 1164286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MDM2	NM_002392.6	c.-94A>G		5_prime_UTR_variant	Exon 1 of 11	ENST00000258149.11	NP_002383.2
MDM2	NM_001145339.2	c.-94A>G		5_prime_UTR_variant	Exon 1 of 9		NP_001138811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.-94A>G		5_prime_UTR_variant	Exon 1 of 11	1	NM_002392.6	ENSP00000258149.6

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

African (AFR) AF: 0.343 AC: 10992 AN: 32016

American (AMR) AF: 0.211 AC: 9275 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 7476 AN: 25692

East Asian (EAS) AF: 0.284 AC: 11106 AN: 39092

South Asian (SAS) AF: 0.239 AC: 20226 AN: 84480

European-Finnish (FIN) AF: 0.419 AC: 21754 AN: 51972

Middle Eastern (MID) AF: 0.248 AC: 1242 AN: 5004

European-Non Finnish (NFE) AF: 0.408 AC: 429390 AN: 1053418

Other (OTH) AF: 0.359 AC: 20833 AN: 57964

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

African (AFR) AF: 0.345 AC: 14295 AN: 41462

American (AMR) AF: 0.250 AC: 3825 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1021 AN: 3470

East Asian (EAS) AF: 0.280 AC: 1442 AN: 5154

South Asian (SAS) AF: 0.242 AC: 1164 AN: 4818

European-Finnish (FIN) AF: 0.420 AC: 4446 AN: 10578

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.409 AC: 27768 AN: 67932

Other (OTH) AF: 0.345 AC: 729 AN: 2114

Alfa AF: 0.380 Hom.: 5351

Bravo AF: 0.350

Asia WGS AF: 0.281 AC: 976 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Accelerated tumor formation, susceptibility to Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	18
DANN	Benign	0.75
PhyloP100		1.3
PromoterAI		-0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs937283; hg19: chr12-69202164; COSMIC: COSV50700403; COSMIC: COSV50700403;