1-204538313-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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: Splicing: ADA: 0.1142
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.245

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 -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 GnomAd at 467 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM4	NM_002393.5	c.511+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000367182.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM4	ENST00000367182.8	c.511+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_002393.5	P1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 152190 Hom.: 1 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

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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

Other links and lift over

dbSNP: rs77617818; hg19: chr1-204507441;