NM_001354969.2:c.2093G>A

Variant names:

• chr12-68295336-C-T
• rs139465924
• NM_001354969.2:c.2093G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001354969.2(MDM1):​c.2093G>A​(p.Arg698His) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,612,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MDM1 NM_001354969.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.35
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354969.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM1	NM_001354969.2	MANE Select	c.2093G>A	p.Arg698His	missense	Exon 15 of 15	NP_001341898.1	A0A804HIJ5
	MDM1	NM_017440.6		c.2063G>A	p.Arg688His	missense	Exon 14 of 14	NP_059136.2	Q8TC05-1
	MDM1	NM_001205028.3		c.1958G>A	p.Arg653His	missense	Exon 14 of 14	NP_001191957.1	Q8TC05-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDM1	ENST00000682720.1	MANE Select	c.2093G>A	p.Arg698His	missense	Exon 15 of 15	ENSP00000507100.1	A0A804HIJ5
	MDM1	ENST00000303145.11	TSL:1	c.2063G>A	p.Arg688His	missense	Exon 14 of 14	ENSP00000302537.7	Q8TC05-1
	MDM1	ENST00000540418.5	TSL:1	n.*1557G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000443815.2	F5H804

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250506 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1460518 Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24 AN XY: 726560

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000449 AC: 2 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111348

Other (OTH) AF: 0.0000166 AC: 1 AN: 60310

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.4
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.33
MPC		0.34
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.42
gMVP		0.26
Mutation Taster		=73/27	polymorphism

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: rs139465924; hg19: chr12-68689116;