rs962976

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001354969.2(MDM1):c.308C>T(p.Thr103Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,613,840 control chromosomes in the GnomAD database, including 410,347 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T103S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.73 ( 40523 hom., cov: 31)

Exomes 𝑓: 0.71 ( 369824 hom. )

Consequence

MDM1
NM_001354969.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0860

Publications

44 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3557108E-6).

BP6

Variant 12-68326847-G-A is Benign according to our data. Variant chr12-68326847-G-A is described in ClinVar as Benign. ClinVar VariationId is 1247123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MDM1	NM_001354969.2	MANE Select	c.308C>T	p.Thr103Ile	missense	Exon 3 of 15	NP_001341898.1
MDM1	NM_017440.6		c.308C>T	p.Thr103Ile	missense	Exon 3 of 14	NP_059136.2
MDM1	NM_001205028.3		c.308C>T	p.Thr103Ile	missense	Exon 3 of 14	NP_001191957.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MDM1	ENST00000682720.1	MANE Select	c.308C>T	p.Thr103Ile	missense	Exon 3 of 15	ENSP00000507100.1
MDM1	ENST00000303145.11	TSL:1	c.308C>T	p.Thr103Ile	missense	Exon 3 of 14	ENSP00000302537.7
MDM1	ENST00000430606.3	TSL:1	c.308C>T	p.Thr103Ile	missense	Exon 3 of 3	ENSP00000408694.2

Frequencies

GnomAD3 genomes

AF:

0.727

AC:

110385

AN:

151928

Hom.:

40486

Cov.:

show subpopulations

Gnomad AFR

AF:

0.791

Gnomad AMI

AF:

0.828

Gnomad AMR

AF:

0.722

Gnomad ASJ

AF:

0.753

Gnomad EAS

AF:

0.450

Gnomad SAS

AF:

0.682

Gnomad FIN

AF:

0.738

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.708

Gnomad OTH

AF:

0.742

GnomAD2 exomes

AF:

0.693

AC:

174311

AN:

251384

AF XY:

0.696

show subpopulations

Gnomad AFR exome

AF:

0.797

Gnomad AMR exome

AF:

0.676

Gnomad ASJ exome

AF:

0.755

Gnomad EAS exome

AF:

0.413

Gnomad FIN exome

AF:

0.731

Gnomad NFE exome

AF:

0.714

Gnomad OTH exome

AF:

0.716

GnomAD4 exome

AF:

0.710

AC:

1037675

AN:

1461794

Hom.:

369824

Cov.:

AF XY:

0.711

AC XY:

516725

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.795

AC:

26617

AN:

33478

American (AMR)

AF:

0.686

AC:

30670

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.756

AC:

19748

AN:

26134

East Asian (EAS)

AF:

0.516

AC:

20477

AN:

39694

South Asian (SAS)

AF:

0.701

AC:

60482

AN:

86254

European-Finnish (FIN)

AF:

0.724

AC:

38699

AN:

53416

Middle Eastern (MID)

AF:

0.775

AC:

4470

AN:

5768

European-Non Finnish (NFE)

AF:

0.714

AC:

793959

AN:

1111938

Other (OTH)

AF:

0.705

AC:

42553

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

17653

35306

52960

70613

88266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19818

39636

59454

79272

99090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.727

AC:

110477

AN:

152046

Hom.:

40523

Cov.:

AF XY:

0.726

AC XY:

53923

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.791

AC:

32803

AN:

41470

American (AMR)

AF:

0.722

AC:

11034

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.753

AC:

2613

AN:

3470

East Asian (EAS)

AF:

0.449

AC:

2316

AN:

5162

South Asian (SAS)

AF:

0.683

AC:

3296

AN:

4828

European-Finnish (FIN)

AF:

0.738

AC:

7793

AN:

10562

Middle Eastern (MID)

AF:

0.752

AC:

221

AN:

294

European-Non Finnish (NFE)

AF:

0.708

AC:

48088

AN:

67962

Other (OTH)

AF:

0.739

AC:

1558

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1519

3038

4557

6076

7595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

834

1668

2502

3336

4170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.716

Hom.:

153187

Bravo

AF:

0.728

TwinsUK

AF:

0.703

AC:

2606

ALSPAC

AF:

0.708

AC:

2728

ESP6500AA

AF:

0.785

AC:

3459

ESP6500EA

AF:

0.714

AC:

6138

ExAC

AF:

0.695

AC:

84320

Asia WGS

AF:

0.579

AC:

2017

AN:

3478

EpiCase

AF:

0.716

EpiControl

AF:

0.716

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0000014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-0.086

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.6

REVEL

Benign

0.15

Sift

Uncertain

0.027

Sift4G

Benign

0.14

Polyphen

0.80

Vest4

0.024

MPC

0.065

ClinPred

0.0083

GERP RS

0.26

Varity_R

0.059

gMVP

0.14

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over