dbSNP rs181171068: MDM4:p.Pro32Arg (chr1-204526376-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002393.5(MDM4):c.95C>G(p.Pro32Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P32L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MDM4
NM_002393.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.01

Variant links:

Genes affected

MDM4 (HGNC:6974): (MDM4 regulator of p53) This gene encodes a nuclear protein that contains a p53 binding domain at the N-terminus and a RING finger domain at the C-terminus, and shows structural similarity to p53-binding protein MDM2. Both proteins bind the p53 tumor suppressor protein and inhibit its activity, and have been shown to be overexpressed in a variety of human cancers. However, unlike MDM2 which degrades p53, this protein inhibits p53 by binding its transcriptional activation domain. This protein also interacts with MDM2 protein via the RING finger domain, and inhibits the latter's degradation. So this protein can reverse MDM2-targeted degradation of p53, while maintaining suppression of p53 transactivation and apoptotic functions. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2011]

MDM4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29566061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5 link	c.95C>G	p.Pro32Arg	missense_variant	Exon 3 of 11	ENST00000367182.8	NP_002384.2	O15151-1Q59FS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8 link	c.95C>G	p.Pro32Arg	missense_variant	Exon 3 of 11	1	NM_002393.5	ENSP00000356150.3		O15151-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727142

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

0.0027

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

.;.;.;.;T;.;T;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;.;D;D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.30

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

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

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.6

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

REVEL

Benign

0.14

Sift

Benign

0.065

.;T;.;T;T;.;T;T

Sift4G

Benign

0.22

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

Polyphen

0.85

.;.;.;.;P;.;.;.

Vest4

0.55

MutPred

0.58

Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);

MVP

0.50

MPC

2.4

ClinPred

0.96

GERP RS

4.5

Varity_R

0.27

gMVP

0.64

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over