1-204546735-C-T

Variant names:

• chr1-204546735-C-T
• rs2290855
• NM_002393.5:c.823-62C>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.823-62C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 1,106,654 control chromosomes in the GnomAD database, including 248,355 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 (27511 hom., cov: 32)
  • Exomes 𝑓: 0.67 (220844 hom.)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 7 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=-0.86).
• 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.823-62C>T		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.823-62C>T		intron_variant	Intron 9 of 10	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87088 AN: 151862 Hom.: 27507 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.582

GnomAD4 exome AF: 0.675 AC: 644216 AN: 954672 Hom.: 220844 AF XY: 0.673 AC XY: 331964 AN XY: 493186

African (AFR) AF: 0.275 AC: 5972 AN: 21716

American (AMR) AF: 0.615 AC: 20923 AN: 33994

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 13115 AN: 21236

East Asian (EAS) AF: 0.719 AC: 26234 AN: 36510

South Asian (SAS) AF: 0.595 AC: 41638 AN: 69976

European-Finnish (FIN) AF: 0.789 AC: 40912 AN: 51858

Middle Eastern (MID) AF: 0.605 AC: 2795 AN: 4618

European-Non Finnish (NFE) AF: 0.692 AC: 465003 AN: 671952

Other (OTH) AF: 0.645 AC: 27624 AN: 42812

GnomAD4 genome AF: 0.573 AC: 87106 AN: 151982 Hom.: 27511 Cov.: 32 AF XY: 0.580 AC XY: 43087 AN XY: 74274

African (AFR) AF: 0.286 AC: 11853 AN: 41412

American (AMR) AF: 0.599 AC: 9147 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2098 AN: 3470

East Asian (EAS) AF: 0.679 AC: 3506 AN: 5166

South Asian (SAS) AF: 0.597 AC: 2878 AN: 4820

European-Finnish (FIN) AF: 0.811 AC: 8570 AN: 10572

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.691 AC: 46960 AN: 67976

Other (OTH) AF: 0.577 AC: 1214 AN: 2104

Alfa AF: 0.670 Hom.: 15022

Bravo AF: 0.545

Asia WGS AF: 0.591 AC: 2055 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.45
DANN	Benign	0.45
PhyloP100		-1.1
Mutation Taster		=12/88	disease causing

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: rs2290855; hg19: chr1-204515863; COSMIC: COSV65795031; COSMIC: COSV65795031;