1-204546897-A-G

Variant names:

• chr1-204546897-A-G
• rs2290854
• NM_002393.5:c.903+20A>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+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
• Publications: 43 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=-0.89).
• 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 rank	MANE	Protein	UniProt
MDM4	NM_002393.5	c.903+20A>G		intron_variant	Intron 10 of 10	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.903+20A>G		intron_variant	Intron 10 of 10	1	NM_002393.5	ENSP00000356150.3

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

GnomAD2 exomes AF: 0.651 AC: 160365 AN: 246446 AF XY: 0.656

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 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

African (AFR) AF: 0.276 AC: 8515 AN: 30874

American (AMR) AF: 0.620 AC: 27132 AN: 43772

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 16050 AN: 25464

East Asian (EAS) AF: 0.717 AC: 27959 AN: 38998

South Asian (SAS) AF: 0.600 AC: 49999 AN: 83396

European-Finnish (FIN) AF: 0.791 AC: 42127 AN: 53268

Middle Eastern (MID) AF: 0.617 AC: 3453 AN: 5600

European-Non Finnish (NFE) AF: 0.697 AC: 717884 AN: 1030122

Other (OTH) AF: 0.650 AC: 37095 AN: 57082

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

African (AFR) AF: 0.287 AC: 11893 AN: 41462

American (AMR) AF: 0.603 AC: 9213 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2130 AN: 3470

East Asian (EAS) AF: 0.680 AC: 3523 AN: 5178

South Asian (SAS) AF: 0.601 AC: 2895 AN: 4818

European-Finnish (FIN) AF: 0.811 AC: 8588 AN: 10584

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.696 AC: 47352 AN: 67986

Other (OTH) AF: 0.581 AC: 1226 AN: 2110

Alfa AF: 0.654 Hom.: 135475

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
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2290854; hg19: chr1-204516025; COSMIC: COSV65794941; COSMIC: COSV65794941;