1-204556440-G-T

Variant names:

• chr1-204556440-G-T
• rs10900598
• NM_002393.5:c.*6758G>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.*6758G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 225,642 control chromosomes in the GnomAD database, including 20,273 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 0.38 (13028 hom., cov: 32)
  • Exomes 𝑓: 0.43 (7245 hom.)
• Consequence: MDM4 NM_002393.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.571
• Publications: 24 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5	c.*6758G>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.*6758G>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57715 AN: 151886 Hom.: 13022 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.397

GnomAD4 exome AF: 0.432 AC: 31780 AN: 73638 Hom.: 7245 Cov.: 0 AF XY: 0.432 AC XY: 14719 AN XY: 34046

African (AFR) AF: 0.138 AC: 484 AN: 3500

American (AMR) AF: 0.492 AC: 1099 AN: 2232

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 2102 AN: 4632

East Asian (EAS) AF: 0.328 AC: 3466 AN: 10560

South Asian (SAS) AF: 0.350 AC: 224 AN: 640

European-Finnish (FIN) AF: 0.500 AC: 31 AN: 62

Middle Eastern (MID) AF: 0.382 AC: 166 AN: 434

European-Non Finnish (NFE) AF: 0.474 AC: 21522 AN: 45414

Other (OTH) AF: 0.436 AC: 2686 AN: 6164

GnomAD4 genome AF: 0.380 AC: 57726 AN: 152004 Hom.: 13028 Cov.: 32 AF XY: 0.385 AC XY: 28610 AN XY: 74296

African (AFR) AF: 0.127 AC: 5266 AN: 41486

American (AMR) AF: 0.472 AC: 7213 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1530 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1523 AN: 5158

South Asian (SAS) AF: 0.367 AC: 1762 AN: 4806

European-Finnish (FIN) AF: 0.577 AC: 6091 AN: 10548

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32852 AN: 67942

Other (OTH) AF: 0.391 AC: 826 AN: 2112

Alfa AF: 0.383 Hom.: 1949

Bravo AF: 0.364

Asia WGS AF: 0.320 AC: 1114 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.49
DANN	Benign	0.43
PhyloP100		-0.57
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: rs10900598; hg19: chr1-204525568;