12-68302863-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001354969.2(MDM1):​c.1759C>T​(p.Arg587Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,255,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000065 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

MDM1
NM_001354969.2 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.322
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11483419).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MDM1NM_001354969.2 linkc.1759C>T p.Arg587Cys missense_variant Exon 13 of 15 ENST00000682720.1 NP_001341898.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MDM1ENST00000682720.1 linkc.1759C>T p.Arg587Cys missense_variant Exon 13 of 15 NM_001354969.2 ENSP00000507100.1 A0A804HIJ5

Frequencies

GnomAD3 genomes
AF:
0.0000645
AC:
8
AN:
123952
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000586
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000973
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000356
AC:
6
AN:
168576
Hom.:
0
AF XY:
0.0000532
AC XY:
5
AN XY:
93980
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000101
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000585
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000645
AC:
73
AN:
1131278
Hom.:
0
Cov.:
33
AF XY:
0.0000595
AC XY:
33
AN XY:
554326
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000360
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000256
Gnomad4 NFE exome
AF:
0.0000779
Gnomad4 OTH exome
AF:
0.0000225
GnomAD4 genome
AF:
0.0000645
AC:
8
AN:
123952
Hom.:
0
Cov.:
30
AF XY:
0.0000872
AC XY:
5
AN XY:
57366
show subpopulations
Gnomad4 AFR
AF:
0.0000586
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000973
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000992
Hom.:
0
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 04, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1729C>T (p.R577C) alteration is located in exon 12 (coding exon 12) of the MDM1 gene. This alteration results from a C to T substitution at nucleotide position 1729, causing the arginine (R) at amino acid position 577 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
15
DANN
Benign
0.97
DEOGEN2
Benign
0.38
T;T;.
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.054
N
LIST_S2
Benign
0.79
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;.;.
PrimateAI
Benign
0.21
T
PROVEAN
Uncertain
-2.9
D;D;N
REVEL
Benign
0.060
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.015
D;D;D
Polyphen
0.039
B;.;.
Vest4
0.14
MVP
0.30
MPC
0.33
ClinPred
0.26
T
GERP RS
3.6
Varity_R
0.096
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370844986; hg19: chr12-68696643; COSMIC: COSV57447647; API