Variant 1-204530752-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_002393.5(MDM4):c.222A>T(p.Val74=) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.28

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	UniProt
MDM4	NM_002393.5 linkuse as main transcript	c.222A>T	p.Val74=	synonymous_variant	4/11	ENST00000367182.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM4	ENST00000367182.8 linkuse as main transcript	c.222A>T	p.Val74=	synonymous_variant	4/11	1	NM_002393.5	P1	O15151-1

Frequencies

GnomAD3 genomes

AF:

0.00729

AC:

1109

AN:

152212

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00663

AC:

1667

AN:

251482

Hom.:

AF XY:

0.00660

AC XY:

897

AN XY:

135918

show subpopulations

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 SAS exome

AF:

0.000784

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.:

Cov.:

AF XY:

0.00819

AC XY:

5957

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000951

Gnomad4 FIN exome

AF:

0.0159

Gnomad4 NFE exome

AF:

0.00959

Gnomad4 OTH exome

AF:

0.00661

GnomAD4 genome

AF:

0.00729

AC:

1110

AN:

152330

Hom.:

Cov.:

AF XY:

0.00790

AC XY:

588

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.0174

Gnomad4 NFE

AF:

0.00972

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00898

Hom.:

Bravo

AF:

0.00634

Asia WGS

AF:

0.00202

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	MDM4: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.56

DANN

Benign

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over