chr1-204549118-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002393.5(MDM4):​c.909G>A​(p.Glu303=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,592,810 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 14 hom., cov: 33)
Exomes 𝑓: 0.0021 ( 100 hom. )

Consequence

MDM4
NM_002393.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.428
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 1-204549118-G-A is Benign according to our data. Variant chr1-204549118-G-A is described in ClinVar as [Benign]. Clinvar id is 770500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.428 with no splicing effect.
BA1
GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MDM4NM_002393.5 linkuse as main transcriptc.909G>A p.Glu303= synonymous_variant 11/11 ENST00000367182.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MDM4ENST00000367182.8 linkuse as main transcriptc.909G>A p.Glu303= synonymous_variant 11/111 NM_002393.5 P1O15151-1

Frequencies

GnomAD3 genomes
AF:
0.00359
AC:
546
AN:
152176
Hom.:
14
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00150
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0312
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00984
AC:
2365
AN:
240306
Hom.:
82
AF XY:
0.00712
AC XY:
924
AN XY:
129798
show subpopulations
Gnomad AFR exome
AF:
0.00174
Gnomad AMR exome
AF:
0.0707
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000911
Gnomad OTH exome
AF:
0.00749
GnomAD4 exome
AF:
0.00205
AC:
2959
AN:
1440516
Hom.:
100
Cov.:
29
AF XY:
0.00169
AC XY:
1211
AN XY:
716478
show subpopulations
Gnomad4 AFR exome
AF:
0.000886
Gnomad4 AMR exome
AF:
0.0668
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000273
Gnomad4 OTH exome
AF:
0.00153
GnomAD4 genome
AF:
0.00359
AC:
547
AN:
152294
Hom.:
14
Cov.:
33
AF XY:
0.00416
AC XY:
310
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00149
Gnomad4 AMR
AF:
0.0313
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00122
Hom.:
2
Bravo
AF:
0.00682
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeMar 05, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
5.5
DANN
Benign
0.43
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs4252740; hg19: chr1-204518246; API