Genetic Variant MDM2:c.359-105T>G (chr12-68824258-T-G) – 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.359-105T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 698,556 control chromosomes in the GnomAD database, including 69,608 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 0.43 ( 14786 hom., cov: 32)

Exomes 𝑓: 0.44 ( 54822 hom. )

Consequence

MDM2
NM_002392.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.370

Publications

9 publications found

Variant links:

COSMIC-nc: COSV99254363

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:

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=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6 link	c.359-105T>G		intron_variant	Intron 5 of 10	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.359-105T>G		intron_variant	Intron 5 of 10	1	NM_002392.6	ENSP00000258149.6		Q00987-11

Frequencies

GnomAD3 genomes

AF:

0.434

AC:

65938

AN:

151872

Hom.:

14774

Cov.:

show subpopulations

Gnomad AFR

AF:

0.419

Gnomad AMI

AF:

0.430

Gnomad AMR

AF:

0.532

Gnomad ASJ

AF:

0.529

Gnomad EAS

AF:

0.664

Gnomad SAS

AF:

0.609

Gnomad FIN

AF:

0.473

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.380

Gnomad OTH

AF:

0.452

GnomAD4 exome

AF:

0.437

AC:

238584

AN:

546566

Hom.:

54822

Cov.:

AF XY:

0.445

AC XY:

127219

AN XY:

285920

show subpopulations

African (AFR)

AF:

0.411

AC:

5708

AN:

13898

American (AMR)

AF:

0.572

AC:

9511

AN:

16636

Ashkenazi Jewish (ASJ)

AF:

0.526

AC:

8066

AN:

15328

East Asian (EAS)

AF:

0.670

AC:

20808

AN:

31060

South Asian (SAS)

AF:

0.609

AC:

28512

AN:

46800

European-Finnish (FIN)

AF:

0.468

AC:

21439

AN:

45792

Middle Eastern (MID)

AF:

0.493

AC:

1146

AN:

2326

European-Non Finnish (NFE)

AF:

0.378

AC:

130737

AN:

346220

Other (OTH)

AF:

0.444

AC:

12657

AN:

28506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

6420

12840

19260

25680

32100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1866

3732

5598

7464

9330

<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:

0.434

AC:

65982

AN:

151990

Hom.:

14786

Cov.:

AF XY:

0.444

AC XY:

32983

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.419

AC:

17356

AN:

41430

American (AMR)

AF:

0.532

AC:

8135

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.529

AC:

1837

AN:

3472

East Asian (EAS)

AF:

0.664

AC:

3438

AN:

5180

South Asian (SAS)

AF:

0.610

AC:

2944

AN:

4830

European-Finnish (FIN)

AF:

0.473

AC:

4990

AN:

10552

Middle Eastern (MID)

AF:

0.445

AC:

130

AN:

292

European-Non Finnish (NFE)

AF:

0.380

AC:

25812

AN:

67936

Other (OTH)

AF:

0.451

AC:

950

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1874

3748

5623

7497

9371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.403

Hom.:

22833

Bravo

AF:

0.438

Asia WGS

AF:

0.600

AC:

2085

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.61

PhyloP100

0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=11/89

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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