chr12-68302653-C-A

Variant names:

• chr12-68302653-C-A
• rs764264561
• NM_001354969.2:c.1969G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001354969.2(MDM1):​c.1969G>T​(p.Gly657Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MDM1 NM_001354969.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

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.1969G>T	p.Gly657Cys	missense	Exon 13 of 15	NP_001341898.1	A0A804HIJ5
	MDM1	NM_017440.6		c.1939G>T	p.Gly647Cys	missense	Exon 12 of 14	NP_059136.2	Q8TC05-1
	MDM1	NM_001205028.3		c.1834G>T	p.Gly612Cys	missense	Exon 12 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.1969G>T	p.Gly657Cys	missense	Exon 13 of 15	ENSP00000507100.1	A0A804HIJ5
	MDM1	ENST00000303145.11	TSL:1	c.1939G>T	p.Gly647Cys	missense	Exon 12 of 14	ENSP00000302537.7	Q8TC05-1
	MDM1	ENST00000540418.5	TSL:1	n.*1433G>T		non_coding_transcript_exon	Exon 11 of 13	ENSP00000443815.2	F5H804

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461506 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727072

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111756

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

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	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.44		Gain of catalytic residue at R650 (P = 0.0193)
MVP		0.80
MPC		0.33
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.00090	Neutral
Varity_R		0.86
gMVP		0.37
Mutation Taster		=24/76	disease causing

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: rs764264561; hg19: chr12-68696433;