Genetic Variant NM_002392.6:c.14+344T>A (chr12-68808835-T-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.14+344T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 844,256 control chromosomes in the GnomAD database, including 527 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 0.045 ( 327 hom., cov: 33)

Exomes 𝑓: 0.017 ( 200 hom. )

Consequence

MDM2
NM_002392.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.604

Publications

17 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:

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=-0.63).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6 link	c.14+344T>A		intron_variant	Intron 1 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.14+344T>A		intron_variant	Intron 1 of 10	1	NM_002392.6	ENSP00000258149.6		Q00987-11

Frequencies

GnomAD3 genomes

AF:

0.0453

AC:

6895

AN:

152158

Hom.:

326

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.0220

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0335

GnomAD4 exome

AF:

0.0174

AC:

12027

AN:

691980

Hom.:

200

AF XY:

0.0173

AC XY:

5560

AN XY:

321930

show subpopulations

African (AFR)

AF:

0.135

AC:

1753

AN:

12962

American (AMR)

AF:

0.00998

AC:

AN:

802

Ashkenazi Jewish (ASJ)

AF:

0.00594

AC:

AN:

4206

East Asian (EAS)

AF:

0.00

AC:

AN:

2924

South Asian (SAS)

AF:

0.00488

AC:

AN:

13530

European-Finnish (FIN)

AF:

0.0185

AC:

AN:

216

Middle Eastern (MID)

AF:

0.0212

AC:

AN:

1322

European-Non Finnish (NFE)

AF:

0.0154

AC:

9757

AN:

633514

Other (OTH)

AF:

0.0172

AC:

386

AN:

22504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

532

1065

1597

2130

2662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.0455

AC:

6924

AN:

152276

Hom.:

327

Cov.:

AF XY:

0.0445

AC XY:

3316

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.124

AC:

5143

AN:

41532

American (AMR)

AF:

0.0193

AC:

295

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00601

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0220

AC:

234

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0165

AC:

1124

AN:

68014

Other (OTH)

AF:

0.0331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

316

631

947

1262

1578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0334

Hom.:

Bravo

AF:

0.0500

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.88

(source)

DANN

Benign

0.74

PhyloP100

-0.60

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.85

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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