dbSNP rs4252697: MDM4:c.343+9C>T (chr1-204532255-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002393.5(MDM4):c.343+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,546,576 control chromosomes in the GnomAD database, including 28,907 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 0.16 ( 2406 hom., cov: 32)

Exomes 𝑓: 0.19 ( 26501 hom. )

Consequence

MDM4
NM_002393.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.311

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5 link	c.343+9C>T		intron_variant	Intron 5 of 10	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.343+9C>T		intron_variant	Intron 5 of 10	1	NM_002393.5	ENSP00000356150.3		O15151-1

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24736

AN:

151972

Hom.:

2408

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0779

Gnomad AMI

AF:

0.141

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.381

Gnomad SAS

AF:

0.233

Gnomad FIN

AF:

0.215

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.160

GnomAD3 exomes

AF:

0.187

AC:

46544

AN:

248742

Hom.:

5131

AF XY:

0.194

AC XY:

26068

AN XY:

134578

show subpopulations

Gnomad AFR exome

AF:

0.0745

Gnomad AMR exome

AF:

0.0715

Gnomad ASJ exome

AF:

0.174

Gnomad EAS exome

AF:

0.389

Gnomad SAS exome

AF:

0.215

Gnomad FIN exome

AF:

0.218

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.188

AC:

261748

AN:

1394484

Hom.:

26501

Cov.:

AF XY:

0.190

AC XY:

132905

AN XY:

697734

show subpopulations

Gnomad4 AFR exome

AF:

0.0712

Gnomad4 AMR exome

AF:

0.0760

Gnomad4 ASJ exome

AF:

0.166

Gnomad4 EAS exome

AF:

0.397

Gnomad4 SAS exome

AF:

0.214

Gnomad4 FIN exome

AF:

0.219

Gnomad4 NFE exome

AF:

0.185

Gnomad4 OTH exome

AF:

0.184

GnomAD4 genome

AF:

0.163

AC:

24730

AN:

152092

Hom.:

2406

Cov.:

AF XY:

0.165

AC XY:

12234

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0778

Gnomad4 AMR

AF:

0.110

Gnomad4 ASJ

AF:

0.163

Gnomad4 EAS

AF:

0.382

Gnomad4 SAS

AF:

0.231

Gnomad4 FIN

AF:

0.215

Gnomad4 NFE

AF:

0.197

Gnomad4 OTH

AF:

0.159

Alfa

AF:

0.182

Hom.:

1532

Bravo

AF:

0.148

Asia WGS

AF:

0.261

AC:

906

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.6

DANN

Benign

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over