chr12-68302862-C-T

Variant names:

• chr12-68302862-C-T
• rs376113390
• NM_001354969.2:c.1760G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001354969.2(MDM1):​c.1760G>A​(p.Arg587His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000794 in 1,348,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R587C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: MDM1 NM_001354969.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.272
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05746129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM1	NM_001354969.2	c.1760G>A	p.Arg587His	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.1760G>A	p.Arg587His	missense_variant	Exon 13 of 15		NM_001354969.2	ENSP00000507100.1

Frequencies

GnomAD3 genomes AF: 0.0000866 AC: 11 AN: 127010 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000383

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: 0.000111

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000346 AC: 6 AN: 173622 AF XY: 0.0000414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000457

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000786 AC: 96 AN: 1221382 Hom.: 0 Cov.: 34 AF XY: 0.0000702 AC XY: 42 AN XY: 598318

African (AFR) AF: 0.00 AC: 0 AN: 26996

American (AMR) AF: 0.000191 AC: 5 AN: 26136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19454

East Asian (EAS) AF: 0.00 AC: 0 AN: 30714

South Asian (SAS) AF: 0.0000560 AC: 3 AN: 53536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4708

European-Non Finnish (NFE) AF: 0.0000867 AC: 84 AN: 969274

Other (OTH) AF: 0.0000829 AC: 4 AN: 48268

GnomAD4 genome AF: 0.0000866 AC: 11 AN: 127010 Hom.: 0 Cov.: 30 AF XY: 0.0000169 AC XY: 1 AN XY: 59272

African (AFR) AF: 0.00 AC: 0 AN: 33996

American (AMR) AF: 0.000383 AC: 4 AN: 10446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3326

East Asian (EAS) AF: 0.00 AC: 0 AN: 4512

South Asian (SAS) AF: 0.00 AC: 0 AN: 3894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.000111 AC: 7 AN: 62998

Other (OTH) AF: 0.00 AC: 0 AN: 1624

Alfa AF: 0.0000571 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1730G>A (p.R577H) alteration is located in exon 12 (coding exon 12) of the MDM1 gene. This alteration results from a G to A substitution at nucleotide position 1730, causing the arginine (R) at amino acid position 577 to be replaced by a histidine (H). 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	0.068
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.2
DANN	Benign	0.91
DEOGEN2	Benign	0.075	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;.;.
PhyloP100		-0.27
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.0050
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.017	B;.;.
Vest4		0.13
MVP		0.072
MPC		0.057
ClinPred		0.025	T
GERP RS		-3.5
PromoterAI		-0.013	Neutral
Varity_R		0.025
gMVP		0.13
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs376113390; hg19: chr12-68696642; COSMIC: COSV57449355;