1-204549248-A-C

Variant names:

• chr1-204549248-A-C
• rs79824231
• NM_002393.5:c.1039A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002393.5(MDM4):​c.1039A>C​(p.Thr347Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MDM4 NM_002393.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• Publications: 4 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: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057307005).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	NM_002393.5	MANE Select	c.1039A>C	p.Thr347Pro	missense	Exon 11 of 11	NP_002384.2
	MDM4	NM_001204171.2		c.889A>C	p.Thr297Pro	missense	Exon 10 of 10	NP_001191100.1
	MDM4	NM_001278517.2		c.745A>C	p.Thr249Pro	missense	Exon 8 of 8	NP_001265446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM4	ENST00000367182.8	TSL:1 MANE Select	c.1039A>C	p.Thr347Pro	missense	Exon 11 of 11	ENSP00000356150.3
	MDM4	ENST00000454264.6	TSL:1	c.889A>C	p.Thr297Pro	missense	Exon 10 of 10	ENSP00000396840.2
	MDM4	ENST00000367183.7	TSL:1	c.79-18A>C		intron	N/A	ENSP00000356151.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.53	N
PhyloP100		2.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.059
Sift	Benign	0.43	T
Sift4G	Benign	0.37	T
Polyphen		0.0070	B
Vest4		0.057
MutPred		0.24		Loss of glycosylation at T347 (P = 0.0225)
MVP		0.24
MPC		0.21
ClinPred		0.099	T
GERP RS		2.4
Varity_R		0.045
gMVP		0.13
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs79824231; hg19: chr1-204518376;