1-204547449-A-G

Variant names:

• chr1-204547449-A-G
• rs1563828
• NM_002393.5:c.903+572A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002393.5(MDM4):​c.903+572A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 151,984 control chromosomes in the GnomAD database, including 26,534 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 0.56 (26534 hom., cov: 32)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.606
• Publications: 33 publications found

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: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	NM_002393.5	MANE Select	c.903+572A>G		intron	N/A	NP_002384.2
	MDM4	NM_001204171.2		c.753+572A>G		intron	N/A	NP_001191100.1
	MDM4	NM_001278517.2		c.609+572A>G		intron	N/A	NP_001265446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	ENST00000367182.8	TSL:1 MANE Select	c.903+572A>G		intron	N/A	ENSP00000356150.3
	MDM4	ENST00000454264.6	TSL:1	c.753+572A>G		intron	N/A	ENSP00000396840.2
	MDM4	ENST00000367183.7	TSL:1	c.79-1817A>G		intron	N/A	ENSP00000356151.3

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85131 AN: 151864 Hom.: 26533 Cov.: 32

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.569

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

GnomAD4 genome AF: 0.560 AC: 85137 AN: 151984 Hom.: 26534 Cov.: 32 AF XY: 0.567 AC XY: 42132 AN XY: 74284

African (AFR) AF: 0.264 AC: 10933 AN: 41420

American (AMR) AF: 0.590 AC: 9014 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2089 AN: 3462

East Asian (EAS) AF: 0.681 AC: 3519 AN: 5170

South Asian (SAS) AF: 0.597 AC: 2879 AN: 4822

European-Finnish (FIN) AF: 0.794 AC: 8393 AN: 10570

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46277 AN: 67962

Other (OTH) AF: 0.563 AC: 1185 AN: 2106

Alfa AF: 0.648 Hom.: 53642

Bravo AF: 0.532

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.57
DANN	Benign	0.72
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1563828; hg19: chr1-204516577;