Genetic Variant NR0B1:p.Arg267His (chrX-30308564-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM5BS2

The NM_000475.5(NR0B1):c.800G>A(p.Arg267His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,093,772 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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. R267P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 2 hem. )

Consequence

NR0B1
NM_000475.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

Publications

5 publications found

Variant links:

Genes affected

NR0B1 (HGNC:7960): (nuclear receptor subfamily 0 group B member 1) This gene encodes a protein that contains a DNA-binding domain. The encoded protein acts as a dominant-negative regulator of transcription which is mediated by the retinoic acid receptor. This protein also functions as an anti-testis gene by acting antagonistically to Sry. Mutations in this gene result in both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism. [provided by RefSeq, Jul 2008]

NR0B1 Gene-Disease associations (from GenCC):

X-linked adrenal hypoplasia congenita
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health
46,XY sex reversal 2
Inheritance: XL Classification: MODERATE Submitted by: Ambry Genetics

NR0B1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-30308564-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000475.5. 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
	NR0B1	NM_000475.5	MANE Select	c.800G>A	p.Arg267His	missense	Exon 1 of 2	NP_000466.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR0B1	ENST00000378970.5	TSL:1 MANE Select	c.800G>A	p.Arg267His	missense	Exon 1 of 2	ENSP00000368253.4	P51843-1
	NR0B1	ENST00000378963.1	TSL:2	c.-86G>A		upstream_gene	N/A	ENSP00000368246.1	A6NNU8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000595

AC:

AN:

168147

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000762

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1093772

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

360202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26362

American (AMR)

AF:

0.00

AC:

AN:

34952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19303

East Asian (EAS)

AF:

0.000199

AC:

AN:

30102

South Asian (SAS)

AF:

0.00

AC:

AN:

53429

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840771

Other (OTH)

AF:

0.00

AC:

AN:

45953

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.63

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

1.3

PhyloP100

1.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.71

Sift

Benign

0.16

Sift4G

Uncertain

0.026

Polyphen

0.99

Vest4

0.17

MutPred

0.60

Gain of methylation at K270 (P = 0.0449)

MVP

0.91

MPC

1.5

ClinPred

0.69

GERP RS

4.6

PromoterAI

-0.0046

Neutral

(source)

Varity_R

0.30

gMVP

0.36

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over