Genetic Variant MDM2:p.Ile25Thr (chr12-68809267-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002392.6(MDM2):c.74T>C(p.Ile25Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MDM2
NM_002392.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.76

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20564607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6 link	c.74T>C	p.Ile25Thr	missense_variant	Exon 2 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.74T>C	p.Ile25Thr	missense_variant	Exon 2 of 11	1	NM_002392.6	ENSP00000258149.6		Q00987-11

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249564

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Accelerated tumor formation, susceptibility to;C5231460:Lessel-kubisch syndrome

Uncertain:1

Jun 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;T;T;T;D;T;.;.;.;.;T;.;.;.;.;.;T;T;.

Eigen

Benign

0.031

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.86

D;T;T;T;D;T;T;T;.;.;.;T;D;T;.;D;D;.;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.94

.;.;.;.;L;.;.;.;.;.;.;L;L;.;.;L;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.55

.;N;N;N;N;N;D;D;N;D;N;N;N;N;D;N;N;N;D

REVEL

Benign

0.19

Sift

Benign

0.030

.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;T;T;.

Sift4G

Benign

0.081

T;D;D;T;D;D;D;D;D;D;D;D;T;T;D;T;D;T;D

Polyphen

0.74

P;.;B;B;B;.;.;.;.;.;B;B;B;B;.;B;.;.;.

Vest4

0.53

MutPred

0.39

.;Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);.;Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);Gain of glycosylation at I19 (P = 0.0184);.;.;

MVP

0.79

ClinPred

0.41

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.17

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over