Genetic Variant MDM2:c.*1777G>A (chr12-68841626-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002392.6(MDM2):c.*1777G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 209,294 control chromosomes in the GnomAD database, including 13,628 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 0.35 ( 9809 hom., cov: 32)

Exomes 𝑓: 0.35 ( 3819 hom. )

Consequence

MDM2
NM_002392.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.570

Publications

21 publications found

Variant links:

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)

MDM2 links:

ENSG00000257181 (HGNC:):

ENSG00000257181 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6 link	c.*1777G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000258149.11	NP_002383.2	Q00987-11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11 link	c.*1777G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_002392.6	ENSP00000258149.6		Q00987-11
ENSG00000257181	ENST00000553141.1 link	n.447C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52691

AN:

151814

Hom.:

9805

Cov.:

show subpopulations

Gnomad AFR

AF:

0.260

Gnomad AMI

AF:

0.521

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.262

Gnomad EAS

AF:

0.281

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.445

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.423

Gnomad OTH

AF:

0.334

GnomAD4 exome

AF:

0.353

AC:

20245

AN:

57362

Hom.:

3819

Cov.:

AF XY:

0.352

AC XY:

9313

AN XY:

26484

show subpopulations

African (AFR)

AF:

0.257

AC:

648

AN:

2520

American (AMR)

AF:

0.238

AC:

397

AN:

1666

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

900

AN:

3672

East Asian (EAS)

AF:

0.279

AC:

2410

AN:

8626

South Asian (SAS)

AF:

0.209

AC:

111

AN:

530

European-Finnish (FIN)

AF:

0.571

AC:

AN:

Middle Eastern (MID)

AF:

0.255

AC:

AN:

368

European-Non Finnish (NFE)

AF:

0.399

AC:

14084

AN:

35278

Other (OTH)

AF:

0.338

AC:

1577

AN:

4660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

645

1290

1934

2579

3224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.347

AC:

52729

AN:

151932

Hom.:

9809

Cov.:

AF XY:

0.344

AC XY:

25568

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.260

AC:

10764

AN:

41428

American (AMR)

AF:

0.244

AC:

3720

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

906

AN:

3464

East Asian (EAS)

AF:

0.281

AC:

1454

AN:

5166

South Asian (SAS)

AF:

0.247

AC:

1190

AN:

4818

European-Finnish (FIN)

AF:

0.445

AC:

4678

AN:

10522

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.423

AC:

28760

AN:

67952

Other (OTH)

AF:

0.335

AC:

705

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1757

3514

5272

7029

8786

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

516

1032

1548

2064

2580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.388

Hom.:

2833

Bravo

AF:

0.329

Asia WGS

AF:

0.284

AC:

985

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.3

(source)

DANN

Benign

0.45

PhyloP100

0.57

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over