rs376113390

Variant names:

• chr12-68302862-C-A
• rs376113390
• NM_001354969.2:c.1760G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-68302862-C-A
• chr12-68302862-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354969.2(MDM1):​c.1760G>T​(p.Arg587Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 127,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R587H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MDM1 NM_001354969.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11628631).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM1	NM_001354969.2	c.1760G>T	p.Arg587Leu	missense_variant	Exon 13 of 15	ENST00000682720.1	NP_001341898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM1	ENST00000682720.1	c.1760G>T	p.Arg587Leu	missense_variant	Exon 13 of 15		NM_001354969.2	ENSP00000507100.1

Frequencies

GnomAD3 genomes AF: 0.0000157 AC: 2 AN: 127004 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000164 AC: 2 AN: 1221374 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 598312

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

African (AFR) AF: 0.00 AC: 0 AN: 26996

American (AMR) AF: 0.00 AC: 0 AN: 26136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19454

East Asian (EAS) AF: 0.00 AC: 0 AN: 30714

South Asian (SAS) AF: 0.00 AC: 0 AN: 53536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4708

European-Non Finnish (NFE) AF: 0.00000206 AC: 2 AN: 969266

Other (OTH) AF: 0.00 AC: 0 AN: 48268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000157 AC: 2 AN: 127004 Hom.: 0 Cov.: 30 AF XY: 0.0000169 AC XY: 1 AN XY: 59268

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

African (AFR) AF: 0.0000294 AC: 1 AN: 33996

American (AMR) AF: 0.00 AC: 0 AN: 10446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3326

East Asian (EAS) AF: 0.00 AC: 0 AN: 4512

South Asian (SAS) AF: 0.00 AC: 0 AN: 3894

European-Finnish (FIN) AF: 0.000194 AC: 1 AN: 5152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62998

Other (OTH) AF: 0.00 AC: 0 AN: 1624

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Benign	0.96
DEOGEN2	Benign	0.39	T;T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Uncertain	0.86	D;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.;.
PhyloP100		-0.27
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.1	N;D;N
REVEL	Benign	0.022
Sift	Uncertain	0.028	D;D;D
Sift4G	Benign	0.10	T;D;T
Polyphen		0.56	P;.;.
Vest4		0.36
MutPred		0.32		Loss of MoRF binding (P = 0.0233);.;.;
MVP		0.22
MPC		0.25
ClinPred		0.54	D
GERP RS		-3.5
PromoterAI		-0.026	Neutral
Varity_R		0.060
gMVP		0.17
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs376113390; hg19: chr12-68696642;