rs74315349
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PVS1_StrongPP5BS2_Supporting
The NM_021969.3(NR0B2):c.100C>T(p.Arg34Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,509,110 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 Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
NR0B2
NM_021969.3 stop_gained
NM_021969.3 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 1.92
Genes affected
NR0B2 (HGNC:7961): (nuclear receptor subfamily 0 group B member 2) The protein encoded by this gene is an unusual orphan receptor that contains a putative ligand-binding domain but lacks a conventional DNA-binding domain. The gene product is a member of the nuclear hormone receptor family, a group of transcription factors regulated by small hydrophobic hormones, a subset of which do not have known ligands and are referred to as orphan nuclear receptors. The protein has been shown to interact with retinoid and thyroid hormone receptors, inhibiting their ligand-dependent transcriptional activation. In addition, interaction with estrogen receptors has been demonstrated, leading to inhibition of function. Studies suggest that the protein represses nuclear hormone receptor-mediated transactivation via two separate steps: competition with coactivators and the direct effects of its transcriptional repressor function. [provided by RefSeq, Jul 2008]
NUDC (HGNC:8045): (nuclear distribution C, dynein complex regulator) This gene encodes a nuclear distribution protein that plays an essential role in mitosis and cytokinesis. The encoded protein is involved in spindle formation during mitosis and in microtubule organization during cytokinesis. Pseudogenes of this gene are found on chromosome 2. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.871 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PP5
?
Variant 1-26913841-G-A is Pathogenic according to our data. Variant chr1-26913841-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5426.Status of the report is no_assertion_criteria_provided, 0 stars.
BS2
?
High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NR0B2 | NM_021969.3 | c.100C>T | p.Arg34Ter | stop_gained | 1/2 | ENST00000254227.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NR0B2 | ENST00000254227.4 | c.100C>T | p.Arg34Ter | stop_gained | 1/2 | 1 | NM_021969.3 | P1 | |
NUDC | ENST00000435827.6 | c.93+2606G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000906 AC: 16AN: 176516Hom.: 0 AF XY: 0.000118 AC XY: 11AN XY: 92976
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GnomAD4 exome AF: 0.0000361 AC: 49AN: 1356948Hom.: 0 Cov.: 31 AF XY: 0.0000362 AC XY: 24AN XY: 662800
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74330
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Obesity, mild, early-onset Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 16, 2001 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at