Genetic Variant MDM1:p.His681Tyr (chr12-68296944-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001354969.2(MDM1):c.2041C>T(p.His681Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,437,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MDM1
NM_001354969.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49

Publications

0 publications found

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]

MDM1 Gene-Disease associations (from GenCC):

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

MDM1 links:

ENSG00000303715 (HGNC:):

ENSG00000303715 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM1	NM_001354969.2 link	c.2041C>T	p.His681Tyr	missense_variant	Exon 14 of 15	ENST00000682720.1	NP_001341898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM1	ENST00000682720.1 link	c.2041C>T	p.His681Tyr	missense_variant	Exon 14 of 15		NM_001354969.2	ENSP00000507100.1		A0A804HIJ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000872

AC:

AN:

229392

AF XY:

0.00000807

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000936

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1437154

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714146

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31930

American (AMR)

AF:

0.00

AC:

AN:

40452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25550

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38774

South Asian (SAS)

AF:

0.00

AC:

AN:

80330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102288

Other (OTH)

AF:

0.0000169

AC:

AN:

59338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.022510), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 11, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2011C>T (p.H671Y) alteration is located in exon 13 (coding exon 13) of the MDM1 gene. This alteration results from a C to T substitution at nucleotide position 2011, causing the histidine (H) at amino acid position 671 to be replaced by a tyrosine (Y). 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

0.089

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

4.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.082

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.056

T;T

Polyphen

0.95

P;.

Vest4

0.30

MutPred

0.26

Gain of catalytic residue at L666 (P = 0.0087);.;

MVP

0.14

MPC

0.12

ClinPred

0.55

GERP RS

5.0

Varity_R

0.12

gMVP

0.082

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: -21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr12-68296944-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over