chr1-204528785-G-C

Variant names:

• chr1-204528785-G-C
• rs2169137
• NM_002393.5:c.154-1899G>C

Variant summary

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

The NM_002393.5(MDM4):​c.154-1899G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,037,618 control chromosomes in the GnomAD database, including 294,697 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 (44700 hom., cov: 31)
  • Exomes 𝑓: 0.75 (249997 hom.)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339
• Publications: 18 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)

LOC100291628 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5	c.154-1899G>C		intron_variant	Intron 3 of 10	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.154-1899G>C		intron_variant	Intron 3 of 10	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes AF: 0.764 AC: 116137 AN: 151950 Hom.: 44678 Cov.: 31

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.961

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.739

GnomAD4 exome AF: 0.749 AC: 662963 AN: 885550 Hom.: 249997 AF XY: 0.748 AC XY: 341106 AN XY: 455834

African (AFR) AF: 0.792 AC: 17509 AN: 22100

American (AMR) AF: 0.751 AC: 27048 AN: 35992

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 14629 AN: 21090

East Asian (EAS) AF: 0.963 AC: 33888 AN: 35172

South Asian (SAS) AF: 0.747 AC: 51308 AN: 68690

European-Finnish (FIN) AF: 0.840 AC: 40925 AN: 48698

Middle Eastern (MID) AF: 0.739 AC: 2253 AN: 3050

European-Non Finnish (NFE) AF: 0.730 AC: 444974 AN: 609876

Other (OTH) AF: 0.744 AC: 30429 AN: 40882

GnomAD4 genome AF: 0.764 AC: 116212 AN: 152068 Hom.: 44700 Cov.: 31 AF XY: 0.771 AC XY: 57290 AN XY: 74340

African (AFR) AF: 0.786 AC: 32563 AN: 41438

American (AMR) AF: 0.730 AC: 11169 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2371 AN: 3470

East Asian (EAS) AF: 0.962 AC: 4975 AN: 5172

South Asian (SAS) AF: 0.752 AC: 3617 AN: 4812

European-Finnish (FIN) AF: 0.866 AC: 9182 AN: 10602

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.733 AC: 49834 AN: 67964

Other (OTH) AF: 0.733 AC: 1548 AN: 2112

Alfa AF: 0.763 Hom.: 5552

Bravo AF: 0.757

Asia WGS AF: 0.807 AC: 2804 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.9
DANN	Benign	0.42
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2169137; hg19: chr1-204497913;