rs4245739

Variant names:

• chr1-204549714-C-A
• rs4245739
• NM_002393.5:c.*32C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-204549714-C-A
• chr1-204549714-C-G
• chr1-204549714-C-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.*32C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,210,462 control chromosomes in the GnomAD database, including 341,577 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 0.76 (44023 hom., cov: 33)
  • Exomes 𝑓: 0.75 (297554 hom.)
• Consequence: MDM4 NM_002393.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.135
• Publications: 231 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5	c.*32C>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.*32C>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115311 AN: 152058 Hom.: 44003 Cov.: 33

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.961

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.734

GnomAD2 exomes AF: 0.772 AC: 124143 AN: 160836 AF XY: 0.767

Gnomad AFR exome AF: 0.769

Gnomad AMR exome AF: 0.759

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.970

Gnomad FIN exome AF: 0.856

Gnomad NFE exome AF: 0.733

Gnomad OTH exome AF: 0.740

GnomAD4 exome AF: 0.748 AC: 792101 AN: 1058286 Hom.: 297554 Cov.: 13 AF XY: 0.748 AC XY: 394976 AN XY: 528202

African (AFR) AF: 0.777 AC: 18671 AN: 24040

American (AMR) AF: 0.753 AC: 17748 AN: 23582

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 12523 AN: 17918

East Asian (EAS) AF: 0.963 AC: 34976 AN: 36308

South Asian (SAS) AF: 0.748 AC: 42848 AN: 57286

European-Finnish (FIN) AF: 0.839 AC: 40166 AN: 47870

Middle Eastern (MID) AF: 0.756 AC: 3549 AN: 4696

European-Non Finnish (NFE) AF: 0.734 AC: 587468 AN: 800848

Other (OTH) AF: 0.747 AC: 34152 AN: 45738

GnomAD4 genome AF: 0.758 AC: 115383 AN: 152176 Hom.: 44023 Cov.: 33 AF XY: 0.765 AC XY: 56886 AN XY: 74384

African (AFR) AF: 0.764 AC: 31695 AN: 41498

American (AMR) AF: 0.728 AC: 11132 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2395 AN: 3470

East Asian (EAS) AF: 0.962 AC: 4987 AN: 5186

South Asian (SAS) AF: 0.752 AC: 3629 AN: 4828

European-Finnish (FIN) AF: 0.866 AC: 9189 AN: 10608

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.733 AC: 49865 AN: 67984

Other (OTH) AF: 0.728 AC: 1539 AN: 2114

Alfa AF: 0.738 Hom.: 148470

Bravo AF: 0.749

Asia WGS AF: 0.805 AC: 2798 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.41
DANN	Benign	0.50
PhyloP100		0.14
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: rs4245739; hg19: chr1-204518842; COSMIC: COSV65795419; COSMIC: COSV65795419;