chr1-204542972-T-C

Variant names:

• chr1-204542972-T-C
• rs4252717
• NM_002393.5:c.672+28T>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.672+28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,580,882 control chromosomes in the GnomAD database, including 354,124 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 (27432 hom., cov: 31)
  • Exomes 𝑓: 0.67 (326692 hom.)
• Consequence: MDM4 NM_002393.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.119
• Publications: 17 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: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	NM_002393.5	MANE Select	c.672+28T>C		intron	N/A	NP_002384.2	O15151-1
	MDM4	NM_001204171.2		c.672+28T>C		intron	N/A	NP_001191100.1	O15151-5
	MDM4	NM_001278517.2		c.378+28T>C		intron	N/A	NP_001265446.1	A0A087WZ58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	ENST00000367182.8	TSL:1 MANE Select	c.672+28T>C		intron	N/A	ENSP00000356150.3	O15151-1
	MDM4	ENST00000454264.6	TSL:1	c.672+28T>C		intron	N/A	ENSP00000396840.2	O15151-5
	MDM4	ENST00000367183.7	TSL:1	c.79-6294T>C		intron	N/A	ENSP00000356151.3	O15151-4

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86778 AN: 151844 Hom.: 27429 Cov.: 31

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.649 AC: 153674 AN: 236734 AF XY: 0.654

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.625

Gnomad ASJ exome AF: 0.626

Gnomad EAS exome AF: 0.690

Gnomad FIN exome AF: 0.799

Gnomad NFE exome AF: 0.690

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.672 AC: 959549 AN: 1428920 Hom.: 326692 Cov.: 25 AF XY: 0.671 AC XY: 476691 AN XY: 710748

African (AFR) AF: 0.261 AC: 8361 AN: 32052

American (AMR) AF: 0.618 AC: 24994 AN: 40454

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 15634 AN: 25280

East Asian (EAS) AF: 0.716 AC: 28231 AN: 39436

South Asian (SAS) AF: 0.596 AC: 49362 AN: 82844

European-Finnish (FIN) AF: 0.789 AC: 41679 AN: 52818

Middle Eastern (MID) AF: 0.610 AC: 3315 AN: 5436

European-Non Finnish (NFE) AF: 0.687 AC: 750172 AN: 1091506

Other (OTH) AF: 0.640 AC: 37801 AN: 59094

GnomAD4 genome AF: 0.571 AC: 86792 AN: 151962 Hom.: 27432 Cov.: 31 AF XY: 0.578 AC XY: 42952 AN XY: 74264

African (AFR) AF: 0.279 AC: 11556 AN: 41410

American (AMR) AF: 0.598 AC: 9134 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2096 AN: 3468

East Asian (EAS) AF: 0.680 AC: 3505 AN: 5158

South Asian (SAS) AF: 0.598 AC: 2883 AN: 4822

European-Finnish (FIN) AF: 0.811 AC: 8568 AN: 10570

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

European-Non Finnish (NFE) AF: 0.691 AC: 46955 AN: 67954

Other (OTH) AF: 0.575 AC: 1213 AN: 2110

Alfa AF: 0.666 Hom.: 16883

Bravo AF: 0.543

Asia WGS AF: 0.588 AC: 2046 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.55
PhyloP100		0.12
PromoterAI		-0.012	Neutral
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: rs4252717; hg19: chr1-204512100; COSMIC: COSV65794912; COSMIC: COSV65794912;