rs4245739

chr1-204549714-C-Achr1-204549714-C-Gchr1-204549714-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002393.5(MDM4):c.*32C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,210,462 control chromosomes in the GnomAD database, including 341,577 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 0.76 (44023 hom., cov: 33)
  • Exomes 𝑓: 0.75 (297554 hom.)
• Consequence: MDM4 NM_002393.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.135

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM4	NM_002393.5	c.*32C>A		3_prime_UTR_variant	11/11	ENST00000367182.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM4	ENST00000367182.8	c.*32C>A		3_prime_UTR_variant	11/11	1	NM_002393.5	P1

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115311 AN: 152058 Hom.: 44003 Cov.: 33

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.961

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.734

GnomAD3 exomes AF: 0.772 AC: 124143 AN: 160836 Hom.: 48323 AF XY: 0.767 AC XY: 66907 AN XY: 87178

Gnomad AFR exome AF: 0.769

Gnomad AMR exome AF: 0.759

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.970

Gnomad SAS exome AF: 0.744

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.733

Gnomad OTH exome AF: 0.740

GnomAD4 exome AF: 0.748 AC: 792101 AN: 1058286 Hom.: 297554 Cov.: 13 AF XY: 0.748 AC XY: 394976 AN XY: 528202

Gnomad4 AFR exome AF: 0.777

Gnomad4 AMR exome AF: 0.753

Gnomad4 ASJ exome AF: 0.699

Gnomad4 EAS exome AF: 0.963

Gnomad4 SAS exome AF: 0.748

Gnomad4 FIN exome AF: 0.839

Gnomad4 NFE exome AF: 0.734

Gnomad4 OTH exome AF: 0.747

GnomAD4 genome AF: 0.758 AC: 115383 AN: 152176 Hom.: 44023 Cov.: 33 AF XY: 0.765 AC XY: 56886 AN XY: 74384

Gnomad4 AFR AF: 0.764

Gnomad4 AMR AF: 0.728

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.962

Gnomad4 SAS AF: 0.752

Gnomad4 FIN AF: 0.866

Gnomad4 NFE AF: 0.733

Gnomad4 OTH AF: 0.728

Alfa AF: 0.728 Hom.: 50343

Bravo AF: 0.749

Asia WGS AF: 0.805 AC: 2798 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.41
Dann	Benign	0.50

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

Other links and lift over

dbSNP: rs4245739; hg19: chr1-204518842; COSMIC: COSV65795419; COSMIC: COSV65795419;