rs1695147

Variant names:

• chr12-68836409-G-T
• rs1695147
• NM_002392.6:c.841-263G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002392.6(MDM2):​c.841-263G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 152,078 control chromosomes in the GnomAD database, including 44,935 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (44935 hom., cov: 32)
• Consequence: MDM2 NM_002392.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.677
• Publications: 9 publications found

Genes affected

MDM2 (HGNC:6973): (MDM2 proto-oncogene) This gene encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. This gene is itself transcriptionally-regulated by p53. Overexpression or amplification of this locus is detected in a variety of different cancers. There is a pseudogene for this gene on chromosome 2. Alternative splicing results in a multitude of transcript variants, many of which may be expressed only in tumor cells. [provided by RefSeq, Jun 2013]

MDM2 Gene-Disease associations (from GenCC):

• Li-Fraumeni syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lessel-kubisch syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM2	NM_002392.6	c.841-263G>T		intron_variant	Intron 9 of 10	ENST00000258149.11	NP_002383.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM2	ENST00000258149.11	c.841-263G>T		intron_variant	Intron 9 of 10	1	NM_002392.6	ENSP00000258149.6

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114916 AN: 151960 Hom.: 44923 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.829

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.882

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.785

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.756 AC: 114970 AN: 152078 Hom.: 44935 Cov.: 32 AF XY: 0.761 AC XY: 56581 AN XY: 74352

African (AFR) AF: 0.535 AC: 22155 AN: 41422

American (AMR) AF: 0.814 AC: 12447 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2907 AN: 3472

East Asian (EAS) AF: 0.829 AC: 4303 AN: 5192

South Asian (SAS) AF: 0.852 AC: 4110 AN: 4824

European-Finnish (FIN) AF: 0.882 AC: 9341 AN: 10596

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57068 AN: 67982

Other (OTH) AF: 0.783 AC: 1649 AN: 2106

Alfa AF: 0.776 Hom.: 11722

Bravo AF: 0.742

Asia WGS AF: 0.813 AC: 2817 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.7
DANN	Benign	0.20
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs1695147; hg19: chr12-69230189;