1-204538313-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002393.5(MDM4):​c.511+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0007 in 1,497,784 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00043 ( 6 hom. )

Consequence

MDM4
NM_002393.5 splice_donor_5th_base, intron

Scores

2
Splicing: ADA: 0.1142
2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.245
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 -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 1-204538313-G-A is Benign according to our data. Variant chr1-204538313-G-A is described in ClinVar as [Benign]. Clinvar id is 777983.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 475 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MDM4NM_002393.5 linkuse as main transcriptc.511+5G>A splice_donor_5th_base_variant, intron_variant ENST00000367182.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MDM4ENST00000367182.8 linkuse as main transcriptc.511+5G>A splice_donor_5th_base_variant, intron_variant 1 NM_002393.5 P1O15151-1

Frequencies

GnomAD3 genomes
AF:
0.00307
AC:
467
AN:
152190
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0105
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
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:
0.0000882
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.000857
AC:
213
AN:
248470
Hom.:
0
AF XY:
0.000714
AC XY:
96
AN XY:
134416
show subpopulations
Gnomad AFR exome
AF:
0.0111
Gnomad AMR exome
AF:
0.000530
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000992
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000107
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.000427
AC:
574
AN:
1345476
Hom.:
6
Cov.:
21
AF XY:
0.000386
AC XY:
261
AN XY:
675800
show subpopulations
Gnomad4 AFR exome
AF:
0.0138
Gnomad4 AMR exome
AF:
0.000636
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000955
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000358
Gnomad4 OTH exome
AF:
0.00101
GnomAD4 genome
AF:
0.00312
AC:
475
AN:
152308
Hom.:
2
Cov.:
32
AF XY:
0.00285
AC XY:
212
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.0107
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.000784
Hom.:
2
Bravo
AF:
0.00360
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

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 testingLabcorp Genetics (formerly Invitae), LabcorpMar 29, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
8.3
DANN
Benign
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.11
dbscSNV1_RF
Benign
0.44
SpliceAI score (max)
0.060
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: rs77617818; hg19: chr1-204507441; API