rs2306392

Positions:

• chr12-68313507-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354969.2(MDM1):​c.1685C>T​(p.Pro562Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,611,628 control chromosomes in the GnomAD database, including 72,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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: 𝑓 0.24 (4812 hom., cov: 32)
  • Exomes 𝑓: 0.30 (67410 hom.)
• Consequence: MDM1 NM_001354969.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10

Genes affected

MDM1 (HGNC:29917): (Mdm1 nuclear protein) This gene encodes a microtubule-binding nuclear protein that localizes to the centrioles of dividing cells and differentiating multiciliated cells and negatively regulates centriole duplication. The encoded protein is closely associated with the centriole barrel, and resides in the centriole lumen. Naturally-occurring mutations in the orthologous mouse gene are associated with age-related retinal degeneration. [provided by RefSeq, Feb 2019]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005428165).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDM1	NM_001354969.2	c.1685C>T	p.Pro562Leu	missense_variant	12/15	ENST00000682720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDM1	ENST00000682720.1	c.1685C>T	p.Pro562Leu	missense_variant	12/15		NM_001354969.2	P1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35956 AN: 151990 Hom.: 4816 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.282

GnomAD3 exomes AF: 0.272 AC: 68261 AN: 251250 Hom.: 10171 AF XY: 0.285 AC XY: 38670 AN XY: 135796

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.158

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.298 AC: 435356 AN: 1459518 Hom.: 67410 Cov.: 33 AF XY: 0.302 AC XY: 219250 AN XY: 726150

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.380

Gnomad4 EAS exome AF: 0.187

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.201

Gnomad4 NFE exome AF: 0.308

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.236 AC: 35961 AN: 152110 Hom.: 4812 Cov.: 32 AF XY: 0.232 AC XY: 17267 AN XY: 74370

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.284

Alfa AF: 0.302 Hom.: 18485

Bravo AF: 0.234

TwinsUK AF: 0.311 AC: 1155

ALSPAC AF: 0.306 AC: 1181

ESP6500AA AF: 0.126 AC: 557

ESP6500EA AF: 0.313 AC: 2693

ExAC AF: 0.275 AC: 33352

Asia WGS AF: 0.273 AC: 955 AN: 3478

EpiCase AF: 0.327

EpiControl AF: 0.326

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Benign	0.23
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.99	L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Benign	0.12
Sift	Benign	0.47	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0030	B;.
Vest4		0.032
MPC		0.048
ClinPred		0.016	T
GERP RS		2.2
Varity_R		0.028
gMVP		0.098

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: rs2306392; hg19: chr12-68707287; COSMIC: COSV57444838; COSMIC: COSV57444838;