chr1-204556440-G-T

Position:

• chr1-204556440-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MDM4	NM_002393.5	c.*6758G>T		3_prime_UTR_variant	11/11	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.*6758G>T		3_prime_UTR_variant	11/11	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

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.492

Gnomad4 ASJ exome AF: 0.454

Gnomad4 EAS exome AF: 0.328

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.474

Gnomad4 OTH exome AF: 0.436

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

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.441

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.367

Gnomad4 FIN AF: 0.577

Gnomad4 NFE AF: 0.484

Gnomad4 OTH AF: 0.391

Alfa AF: 0.334 Hom.: 1171

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs10900598; hg19: chr1-204525568;