1-204546171-G-C

Variant names:

• chr1-204546171-G-C
• rs2369244
• NM_002393.5:c.823-626G>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.823-626G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 151,914 control chromosomes in the GnomAD database, including 26,509 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 0.56 (26509 hom., cov: 31)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.475
• Publications: 11 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 = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5	c.823-626G>C		intron_variant	Intron 9 of 10	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.823-626G>C		intron_variant	Intron 9 of 10	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85087 AN: 151794 Hom.: 26508 Cov.: 31

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.570

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

GnomAD4 genome AF: 0.560 AC: 85093 AN: 151914 Hom.: 26509 Cov.: 31 AF XY: 0.567 AC XY: 42107 AN XY: 74256

African (AFR) AF: 0.264 AC: 10937 AN: 41392

American (AMR) AF: 0.590 AC: 9008 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2094 AN: 3470

East Asian (EAS) AF: 0.680 AC: 3510 AN: 5164

South Asian (SAS) AF: 0.597 AC: 2867 AN: 4802

European-Finnish (FIN) AF: 0.792 AC: 8359 AN: 10556

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46283 AN: 67962

Other (OTH) AF: 0.563 AC: 1186 AN: 2106

Alfa AF: 0.621 Hom.: 3810

Bravo AF: 0.532

Asia WGS AF: 0.585 AC: 2027 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-0.47
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: rs2369244; hg19: chr1-204515299;