rs4252668

Positions:

• chr1-204516444-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.618

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 -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/exons	MANE	Protein	UniProt
MDM4	NM_002393.5	c.-101T>C		5_prime_UTR_variant	1/11	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.-101T>C		5_prime_UTR_variant	1/11	1	NM_002393.5	ENSP00000356150	P1

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152068 Hom.: 7 Cov.: 32

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: 1 AN: 98 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 76

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00739 AC: 1124 AN: 152186 Hom.: 8 Cov.: 32 AF XY: 0.00804 AC XY: 598 AN XY: 74404

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.00981

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00967 Hom.: 1

Bravo AF: 0.00635

Asia WGS AF: 0.00202 AC: 7 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
DANN	Benign	0.49

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: rs4252668; hg19: chr1-204485572;