dbSNP rs4252668: MDM4:c.-101T>C (chr1-204516444-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002393.5(MDM4):c.-101T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 152,284 control chromosomes in the GnomAD database, including 8 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 0.0074 ( 8 hom., cov: 32)

Exomes 𝑓: 0.010 ( 0 hom. )

Consequence

MDM4
NM_002393.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.618

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

bone marrow failure syndrome 6
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

MDM4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS2

High AC in GnomAd4 at 1124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5 link	c.-101T>C		5_prime_UTR_variant	Exon 1 of 11	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8 link	c.-101T>C		5_prime_UTR_variant	Exon 1 of 11	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes

AF:

0.00738

AC:

1123

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00981

Gnomad OTH

AF:

0.00718

GnomAD4 exome

AF:

0.0102

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0122

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00739

AC:

1124

AN:

152186

Hom.:

Cov.:

AF XY:

0.00804

AC XY:

598

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41532

American (AMR)

AF:

0.00680

AC:

104

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0182

AC:

193

AN:

10604

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00981

AC:

667

AN:

67994

Other (OTH)

AF:

0.00853

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

114

170

227

284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00942

Hom.:

Bravo

AF:

0.00635

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.8

(source)

DANN

Benign

0.49

PhyloP100

-0.62

PromoterAI

-0.15

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over