rs74315349

Variant names:

• chr1-26913841-G-A
• rs74315349
• NM_021969.3:c.100C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-26913841-G-A
• chr1-26913841-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_021969.3(NR0B2):​c.100C>T​(p.Arg34*) 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). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: NR0B2 NM_021969.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.92
• Publications: 12 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-26913841-G-A is Pathogenic according to our data. Variant chr1-26913841-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5426.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021969.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR0B2	NM_021969.3	MANE Select	c.100C>T	p.Arg34*	stop_gained	Exon 1 of 2	NP_068804.1	Q15466

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR0B2	ENST00000254227.4	TSL:1 MANE Select	c.100C>T	p.Arg34*	stop_gained	Exon 1 of 2	ENSP00000254227.3	Q15466
	NUDC	ENST00000435827.6	TSL:5	c.93+2606G>A		intron	N/A	ENSP00000404020.2	A0A0A0MSU9

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000906 AC: 16 AN: 176516 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000289

Gnomad EAS exome AF: 0.000885

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000361 AC: 49 AN: 1356948 Hom.: 0 Cov.: 31 AF XY: 0.0000362 AC XY: 24 AN XY: 662800

African (AFR) AF: 0.0000332 AC: 1 AN: 30138

American (AMR) AF: 0.00 AC: 0 AN: 28950

Ashkenazi Jewish (ASJ) AF: 0.000253 AC: 5 AN: 19782

East Asian (EAS) AF: 0.000933 AC: 36 AN: 38598

South Asian (SAS) AF: 0.0000436 AC: 3 AN: 68844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5286

European-Non Finnish (NFE) AF: 0.00000283 AC: 3 AN: 1059940

Other (OTH) AF: 0.0000179 AC: 1 AN: 55796

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000848 AC: 10

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Obesity, mild, early-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		1.9
Vest4		0.31
GERP RS		1.7
PromoterAI		0.0098	Neutral
Mutation Taster		=30/170	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs74315349; hg19: chr1-27240332;