rs4252697

Variant names:

• chr1-204532255-C-T
• rs4252697
• NM_002393.5:c.343+9C>T

Variant summary

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

The NM_002393.5(MDM4):​c.343+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,546,576 control chromosomes in the GnomAD database, including 28,907 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 0.16 (2406 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26501 hom.)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.311
• Publications: 14 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=-0.59).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5	c.343+9C>T		intron_variant	Intron 5 of 10	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.343+9C>T		intron_variant	Intron 5 of 10	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24736 AN: 151972 Hom.: 2408 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.187 AC: 46544 AN: 248742 AF XY: 0.194

Gnomad AFR exome AF: 0.0745

Gnomad AMR exome AF: 0.0715

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.389

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.188 AC: 261748 AN: 1394484 Hom.: 26501 Cov.: 23 AF XY: 0.190 AC XY: 132905 AN XY: 697734

African (AFR) AF: 0.0712 AC: 2299 AN: 32280

American (AMR) AF: 0.0760 AC: 3363 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4274 AN: 25682

East Asian (EAS) AF: 0.397 AC: 15525 AN: 39112

South Asian (SAS) AF: 0.214 AC: 18052 AN: 84332

European-Finnish (FIN) AF: 0.219 AC: 11638 AN: 53172

Middle Eastern (MID) AF: 0.193 AC: 1093 AN: 5656

European-Non Finnish (NFE) AF: 0.185 AC: 194836 AN: 1051888

Other (OTH) AF: 0.184 AC: 10668 AN: 58106

GnomAD4 genome AF: 0.163 AC: 24730 AN: 152092 Hom.: 2406 Cov.: 32 AF XY: 0.165 AC XY: 12234 AN XY: 74344

African (AFR) AF: 0.0778 AC: 3229 AN: 41490

American (AMR) AF: 0.110 AC: 1678 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 565 AN: 3470

East Asian (EAS) AF: 0.382 AC: 1973 AN: 5162

South Asian (SAS) AF: 0.231 AC: 1111 AN: 4816

European-Finnish (FIN) AF: 0.215 AC: 2276 AN: 10570

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13377 AN: 67986

Other (OTH) AF: 0.159 AC: 337 AN: 2114

Alfa AF: 0.187 Hom.: 2176

Bravo AF: 0.148

Asia WGS AF: 0.261 AC: 906 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.6
DANN	Benign	0.63
PhyloP100		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs4252697; hg19: chr1-204501383; COSMIC: COSV65797201; COSMIC: COSV65797201;