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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• bone marrow failure syndrome 6

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	NM_002393.5	MANE Select	c.222A>T	p.Val74Val	synonymous	Exon 4 of 11	NP_002384.2	O15151-1
	MDM4	NM_001204171.2		c.222A>T	p.Val74Val	synonymous	Exon 4 of 10	NP_001191100.1	O15151-5
	MDM4	NM_001278516.2		c.222A>T	p.Val74Val	synonymous	Exon 4 of 10	NP_001265445.1	Q68DC0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	ENST00000367182.8	TSL:1 MANE Select	c.222A>T	p.Val74Val	synonymous	Exon 4 of 11	ENSP00000356150.3	O15151-1
	MDM4	ENST00000454264.6	TSL:1	c.222A>T	p.Val74Val	synonymous	Exon 4 of 10	ENSP00000396840.2	O15151-5
	MDM4	ENST00000367183.7	TSL:1	c.78+5156A>T		intron	N/A	ENSP00000356151.3	O15151-4

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

African (AFR) AF: 0.00212 AC: 71 AN: 33480

American (AMR) AF: 0.00300 AC: 134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000951 AC: 82 AN: 86258

European-Finnish (FIN) AF: 0.0159 AC: 847 AN: 53420

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.00959 AC: 10668 AN: 1112000

Other (OTH) 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

African (AFR) AF: 0.00245 AC: 102 AN: 41576

American (AMR) AF: 0.00680 AC: 104 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.0174 AC: 184 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00972 AC: 661 AN: 68034

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.56
DANN	Benign	0.76
PhyloP100		-3.3
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

Other links and lift over

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