1-204546897-A-G

Position:

• chr1-204546897-A-G

Variant summary

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

The NM_002393.5(MDM4):​c.903+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,520,660 control chromosomes in the GnomAD database, including 347,174 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 0.58 (27912 hom., cov: 32)
  • Exomes 𝑓: 0.68 (319262 hom.)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.335

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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM4	NM_002393.5	c.903+20A>G		intron_variant		ENST00000367182.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM4	ENST00000367182.8	c.903+20A>G		intron_variant		1	NM_002393.5	P1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87689 AN: 151966 Hom.: 27909 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.696

Gnomad OTH AF: 0.586

GnomAD3 exomes AF: 0.651 AC: 160365 AN: 246446 Hom.: 53783 AF XY: 0.656 AC XY: 87387 AN XY: 133300

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.632

Gnomad EAS exome AF: 0.687

Gnomad SAS exome AF: 0.597

Gnomad FIN exome AF: 0.800

Gnomad NFE exome AF: 0.694

Gnomad OTH exome AF: 0.645

GnomAD4 exome AF: 0.680 AC: 930214 AN: 1368576 Hom.: 319262 Cov.: 20 AF XY: 0.678 AC XY: 465262 AN XY: 685806

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.620

Gnomad4 ASJ exome AF: 0.630

Gnomad4 EAS exome AF: 0.717

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.791

Gnomad4 NFE exome AF: 0.697

Gnomad4 OTH exome AF: 0.650

GnomAD4 genome AF: 0.577 AC: 87707 AN: 152084 Hom.: 27912 Cov.: 32 AF XY: 0.584 AC XY: 43388 AN XY: 74348

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.603

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.680

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.811

Gnomad4 NFE AF: 0.696

Gnomad4 OTH AF: 0.581

Alfa AF: 0.670 Hom.: 58854

Bravo AF: 0.549

Asia WGS AF: 0.592 AC: 2059 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.6
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2290854; hg19: chr1-204516025; COSMIC: COSV65794941; COSMIC: COSV65794941;