12-68302863-G-A

Variant names:

• chr12-68302863-G-A
• rs370844986
• NM_001354969.2:c.1759C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R587H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: MDM1 NM_001354969.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.322
• Publications: 0 publications found

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]

MDM1 Gene-Disease associations (from GenCC):

• schizophrenia

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

ENSG00000303715 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
MDM1	NM_001354969.2	c.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
MDM1	ENST00000682720.1	c.1759C>T	p.Arg587Cys	missense_variant	Exon 13 of 15		NM_001354969.2	ENSP00000507100.1

Frequencies

GnomAD3 genomes AF: 0.0000645 AC: 8 AN: 123952 Hom.: 0 Cov.: 30

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

GnomAD2 exomes AF: 0.0000356 AC: 6 AN: 168576 AF XY: 0.0000532

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 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

African (AFR) AF: 0.00 AC: 0 AN: 25428

American (AMR) AF: 0.00 AC: 0 AN: 23780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18112

East Asian (EAS) AF: 0.0000360 AC: 1 AN: 27784

South Asian (SAS) AF: 0.00 AC: 0 AN: 49982

European-Finnish (FIN) AF: 0.0000256 AC: 1 AN: 39000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4238

European-Non Finnish (NFE) AF: 0.0000779 AC: 70 AN: 898564

Other (OTH) AF: 0.0000225 AC: 1 AN: 44390

GnomAD4 genome AF: 0.0000645 AC: 8 AN: 123952 Hom.: 0 Cov.: 30 AF XY: 0.0000872 AC XY: 5 AN XY: 57366

African (AFR) AF: 0.0000586 AC: 2 AN: 34102

American (AMR) AF: 0.00 AC: 0 AN: 9742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3306

East Asian (EAS) AF: 0.00 AC: 0 AN: 4252

South Asian (SAS) AF: 0.00 AC: 0 AN: 3788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.0000973 AC: 6 AN: 61672

Other (OTH) AF: 0.00 AC: 0 AN: 1566

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

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;.;.
PhyloP100		0.32
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
PromoterAI		-0.017	Neutral
Varity_R		0.096
gMVP		0.17
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

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