12-68313550-C-T

Variant names:

• chr12-68313550-C-T
• rs1481107898
• NM_001354969.2:c.1642G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001354969.2(MDM1):​c.1642G>A​(p.Gly548Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,460,644 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: 0.0000014 (0 hom.)
• Consequence: MDM1 NM_001354969.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDM1	NM_001354969.2	c.1642G>A	p.Gly548Ser	missense_variant, splice_region_variant	Exon 12 of 15	ENST00000682720.1	NP_001341898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDM1	ENST00000682720.1	c.1642G>A	p.Gly548Ser	missense_variant, splice_region_variant	Exon 12 of 15		NM_001354969.2	ENSP00000507100.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251022 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460644 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1612G>A (p.G538S) alteration is located in exon 11 (coding exon 11) of the MDM1 gene. This alteration results from a G to A substitution at nucleotide position 1612, causing the glycine (G) at amino acid position 538 to be replaced by a serine (S). 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	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.070	T;T
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.38		Gain of catalytic residue at V536 (P = 0.0054);.;
MVP		0.59
MPC		0.32
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.53
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1481107898; hg19: chr12-68707330;