rs1380576

Positions:

• chr1-204519150-G-C

Variant summary

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

The NM_002393.5(MDM4):​c.-36+2641G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 152,072 control chromosomes in the GnomAD database, including 27,555 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 0.57 (27555 hom., cov: 32)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.81

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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM4	NM_002393.5	c.-36+2641G>C		intron_variant		ENST00000367182.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM4	ENST00000367182.8	c.-36+2641G>C		intron_variant		1	NM_002393.5	P1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87156 AN: 151952 Hom.: 27551 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.581

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.573 AC: 87173 AN: 152072 Hom.: 27555 Cov.: 32 AF XY: 0.580 AC XY: 43135 AN XY: 74334

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.599

Gnomad4 ASJ AF: 0.604

Gnomad4 EAS AF: 0.680

Gnomad4 SAS AF: 0.599

Gnomad4 FIN AF: 0.811

Gnomad4 NFE AF: 0.691

Gnomad4 OTH AF: 0.577

Alfa AF: 0.639 Hom.: 4150

Bravo AF: 0.545

Asia WGS AF: 0.591 AC: 2054 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.40
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: rs1380576; hg19: chr1-204488278;