rs962976

Variant names:

• chr12-68326847-G-A
• rs962976
• NM_001354969.2:c.308C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-68326847-G-A
• chr12-68326847-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/22 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. T103A) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0860

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]

ACMG classification

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM1	NM_001354969.2	c.308C>T	p.Thr103Ile	missense_variant	Exon 3 of 15	ENST00000682720.1	NP_001341898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM1	ENST00000682720.1	c.308C>T	p.Thr103Ile	missense_variant	Exon 3 of 15		NM_001354969.2	ENSP00000507100.1

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110385 AN: 151928 Hom.: 40486 Cov.: 31

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

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.: 65 AF XY: 0.711 AC XY: 516725 AN XY: 727206

Gnomad4 AFR exome AF: 0.795 AC: 26617 AN: 33478

Gnomad4 AMR exome AF: 0.686 AC: 30670 AN: 44722

Gnomad4 ASJ exome AF: 0.756 AC: 19748 AN: 26134

Gnomad4 EAS exome AF: 0.516 AC: 20477 AN: 39694

Gnomad4 SAS exome AF: 0.701 AC: 60482 AN: 86254

Gnomad4 FIN exome AF: 0.724 AC: 38699 AN: 53416

Gnomad4 NFE exome AF: 0.714 AC: 793959 AN: 1111938

Gnomad4 Remaining exome AF: 0.705 AC: 42553 AN: 60390

GnomAD4 genome AF: 0.727 AC: 110477 AN: 152046 Hom.: 40523 Cov.: 31 AF XY: 0.726 AC XY: 53923 AN XY: 74320

Gnomad4 AFR AF: 0.791 AC: 0.791006 AN: 0.791006

Gnomad4 AMR AF: 0.722 AC: 0.722215 AN: 0.722215

Gnomad4 ASJ AF: 0.753 AC: 0.753026 AN: 0.753026

Gnomad4 EAS AF: 0.449 AC: 0.448663 AN: 0.448663

Gnomad4 SAS AF: 0.683 AC: 0.682684 AN: 0.682684

Gnomad4 FIN AF: 0.738 AC: 0.737834 AN: 0.737834

Gnomad4 NFE AF: 0.708 AC: 0.707572 AN: 0.707572

Gnomad4 OTH AF: 0.739 AC: 0.739089 AN: 0.739089

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17903293) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;.;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.50	T;T;T;T
MetaRNN	Benign	0.0000014	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N;N;N;D
REVEL	Benign	0.15
Sift	Uncertain	0.027	D;T;D;D
Sift4G	Benign	0.14	T;T;.;T
Polyphen		0.80	P;.;.;D
Vest4		0.024
MPC		0.065
ClinPred		0.0083	T
GERP RS		0.26
Varity_R		0.059
gMVP		0.14
Mutation Taster		=99/1	polymorphism (auto)

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

LitVar

Other links and lift over

dbSNP: rs962976; hg19: chr12-68720627; COSMIC: COSV57446191; COSMIC: COSV57446191;