1-204549329-A-C

Position:

• chr1-204549329-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002393.5(MDM4):​c.1120A>C​(p.Lys374Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,614,152 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (22 hom.)
• Consequence: MDM4 NM_002393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.46

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053750277).
• BP6: Variant 1-204549329-A-C is Benign according to our data. Variant chr1-204549329-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424927.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 492 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM4	NM_002393.5	c.1120A>C	p.Lys374Gln	missense_variant	11/11	ENST00000367182.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM4	ENST00000367182.8	c.1120A>C	p.Lys374Gln	missense_variant	11/11	1	NM_002393.5	P1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 492 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00415 AC: 1043 AN: 251368 Hom.: 6 AF XY: 0.00411 AC XY: 558 AN XY: 135858

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.00689

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00442 AC: 6459 AN: 1461816 Hom.: 22 Cov.: 32 AF XY: 0.00443 AC XY: 3222 AN XY: 727216

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00272

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.00509

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74488

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00474 Hom.: 6

Bravo AF: 0.00301

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00514 AC: 624

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MDM4: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.083	T;.;.;.;T;T
Eigen	Benign	-0.0055
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0054	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.
MutationTaster	Benign	0.54	D;D;D;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	.;.;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.066	.;.;T;T;T;D
Sift4G	Benign	0.26	T;T;T;T;T;D
Polyphen		0.65	.;.;.;.;P;.
Vest4		0.29
MVP		0.42
MPC		0.22
ClinPred		0.028	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs41299595; hg19: chr1-204518457; COSMIC: COSV100914530; COSMIC: COSV100914530;