NM_002393.5:c.-36+2641G>C

Variant names:

• chr1-204519150-G-C
• rs1380576
• NM_002393.5:c.-36+2641G>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.-36+2641G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 152,072 control chromosomes in the GnomAD database, including 27,555 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 0.57 (27555 hom., cov: 32)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.81
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5	c.-36+2641G>C		intron_variant	Intron 1 of 10	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.-36+2641G>C		intron_variant	Intron 1 of 10	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87156 AN: 151952 Hom.: 27551 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.581

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

GnomAD4 genome AF: 0.573 AC: 87173 AN: 152072 Hom.: 27555 Cov.: 32 AF XY: 0.580 AC XY: 43135 AN XY: 74334

African (AFR) AF: 0.286 AC: 11844 AN: 41472

American (AMR) AF: 0.599 AC: 9147 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2093 AN: 3466

East Asian (EAS) AF: 0.680 AC: 3517 AN: 5170

South Asian (SAS) AF: 0.599 AC: 2886 AN: 4818

European-Finnish (FIN) AF: 0.811 AC: 8586 AN: 10584

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.691 AC: 47003 AN: 67980

Other (OTH) AF: 0.577 AC: 1218 AN: 2112

Alfa AF: 0.639 Hom.: 4150

Bravo AF: 0.545

Asia WGS AF: 0.591 AC: 2054 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.40
DANN	Benign	0.50
PhyloP100		-1.8
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: rs1380576; hg19: chr1-204488278;