1-204530752-A-T

Variant names:

• chr1-204530752-A-T
• rs61749329
• NM_002393.5:c.222A>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002393.5(MDM4):​c.222A>T​(p.Val74Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00827 in 1,614,198 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (65 hom.)
• Consequence: MDM4 NM_002393.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.28

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

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-204530752-A-T is Benign according to our data. Variant chr1-204530752-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 774283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.28 with no splicing effect.
• BS2: High AC in GnomAd4 at 1110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM4	NM_002393.5	c.222A>T	p.Val74Val	synonymous_variant	Exon 4 of 11	ENST00000367182.8	NP_002384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM4	ENST00000367182.8	c.222A>T	p.Val74Val	synonymous_variant	Exon 4 of 11	1	NM_002393.5	ENSP00000356150.3

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 1109 AN: 152212 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00971

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00663 AC: 1667 AN: 251482 AF XY: 0.00660

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.00971

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00837 AC: 12240 AN: 1461868 Hom.: 65 Cov.: 31 AF XY: 0.00819 AC XY: 5957 AN XY: 727232

Gnomad4 AFR exome AF: 0.00212 AC: 71 AN: 33480

Gnomad4 AMR exome AF: 0.00300 AC: 134 AN: 44724

Gnomad4 ASJ exome AF: 0.000383 AC: 10 AN: 26132

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39692

Gnomad4 SAS exome AF: 0.000951 AC: 82 AN: 86258

Gnomad4 FIN exome AF: 0.0159 AC: 847 AN: 53420

Gnomad4 NFE exome AF: 0.00959 AC: 10668 AN: 1112000

Gnomad4 Remaining exome AF: 0.00661 AC: 399 AN: 60394

GnomAD4 genome AF: 0.00729 AC: 1110 AN: 152330 Hom.: 8 Cov.: 33 AF XY: 0.00790 AC XY: 588 AN XY: 74474

Gnomad4 AFR AF: 0.00245 AC: 0.00245334 AN: 0.00245334

Gnomad4 AMR AF: 0.00680 AC: 0.0067965 AN: 0.0067965

Gnomad4 ASJ AF: 0.000576 AC: 0.000576037 AN: 0.000576037

Gnomad4 EAS AF: 0.000385 AC: 0.000385356 AN: 0.000385356

Gnomad4 SAS AF: 0.000828 AC: 0.000827815 AN: 0.000827815

Gnomad4 FIN AF: 0.0174 AC: 0.0173519 AN: 0.0173519

Gnomad4 NFE AF: 0.00972 AC: 0.00971573 AN: 0.00971573

Gnomad4 OTH AF: 0.00851 AC: 0.00851466 AN: 0.00851466

Alfa AF: 0.00898 Hom.: 2

Bravo AF: 0.00634

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MDM4: BP4, BP7, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.56
DANN	Benign	0.76
Mutation Taster		=99/1	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

Publications

LitVar

Other links and lift over

dbSNP: rs61749329; hg19: chr1-204499880; COSMIC: COSV65798272; COSMIC: COSV65798272;