NM_002393.5:c.-101T>C

Variant names:

• chr1-204516444-T-C
• rs4252668
• NM_002393.5:c.-101T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002393.5(MDM4):​c.-101T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 152,284 control chromosomes in the GnomAD database, including 8 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 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: MDM4 NM_002393.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.618
• Publications: 12 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS2: High AC in GnomAd4 at 1124 AD gene.

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.-101T>C		5_prime_UTR	Exon 1 of 11	NP_002384.2
	MDM4	NM_001204171.2		c.-101T>C		5_prime_UTR	Exon 1 of 10	NP_001191100.1
	MDM4	NM_001278517.2		c.-101T>C		5_prime_UTR	Exon 1 of 8	NP_001265446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	ENST00000367182.8	TSL:1 MANE Select	c.-101T>C		5_prime_UTR	Exon 1 of 11	ENSP00000356150.3
	MDM4	ENST00000454264.6	TSL:1	c.-101T>C		5_prime_UTR	Exon 1 of 10	ENSP00000396840.2
	MDM4	ENST00000367183.7	TSL:1	c.-101T>C		5_prime_UTR	Exon 1 of 3	ENSP00000356151.3

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152068 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00981

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.0102 AC: 1 AN: 98 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 76

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 10

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0122 AC: 1 AN: 82

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.00739 AC: 1124 AN: 152186 Hom.: 8 Cov.: 32 AF XY: 0.00804 AC XY: 598 AN XY: 74404

African (AFR) AF: 0.00243 AC: 101 AN: 41532

American (AMR) AF: 0.00680 AC: 104 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00981 AC: 667 AN: 67994

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00942 Hom.: 1

Bravo AF: 0.00635

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.8
DANN	Benign	0.49
PhyloP100		-0.62
PromoterAI		-0.15	Neutral
Mutation Taster		=300/0	polymorphism

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: rs4252668; hg19: chr1-204485572;