Genetic Variant NM_002393.5:c.1066G>C (chr1-204549275-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002393.5(MDM4):c.1066G>C(p.Gly356Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

MDM4
NM_002393.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.19

Publications

0 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: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

MDM4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDM4	NM_002393.5	MANE Select	c.1066G>C	p.Gly356Arg	missense	Exon 11 of 11	NP_002384.2	O15151-1
MDM4	NM_001204171.2		c.916G>C	p.Gly306Arg	missense	Exon 10 of 10	NP_001191100.1	O15151-5
MDM4	NM_001278517.2		c.772G>C	p.Gly258Arg	missense	Exon 8 of 8	NP_001265446.1	A0A087WZ58

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDM4	ENST00000367182.8	TSL:1 MANE Select	c.1066G>C	p.Gly356Arg	missense	Exon 11 of 11	ENSP00000356150.3	O15151-1
MDM4	ENST00000454264.6	TSL:1	c.916G>C	p.Gly306Arg	missense	Exon 10 of 10	ENSP00000396840.2	O15151-5
MDM4	ENST00000367183.7	TSL:1	c.88G>C	p.Gly30Arg	missense	Exon 3 of 3	ENSP00000356151.3	O15151-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.4

PhyloP100

9.2

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.72

MutPred

0.39

Gain of solvent accessibility (P = 0.0456)

MVP

0.86

MPC

0.74

ClinPred

0.98

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.58

Mutation Taster

=24/76

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over