rs193205940

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000475.5(NR0B1):c.376G>A(p.Val126Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,208,542 control chromosomes in the GnomAD database, including 12 homozygotes. There are 335 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 1 hom., 29 hem., cov: 24)

Exomes 𝑓: 0.00093 ( 11 hom. 306 hem. )

Consequence

NR0B1
NM_000475.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -1.41

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038243532).

BP6

Variant X-30308988-C-T is Benign according to our data. Variant chrX-30308988-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225425.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000881 (98/111220) while in subpopulation EAS AF = 0.0279 (96/3445). AF 95% confidence interval is 0.0234. There are 1 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 29 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.376G>A	p.Val126Met	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.376G>A	p.Val126Met	missense	Exon 1 of 2	ENSP00000368253.4	P51843-1

Frequencies

GnomAD3 genomes

AF:

0.000891

AC:

AN:

111168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000938

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0281

Gnomad SAS

AF:

0.000378

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00279

AC:

497

AN:

178138

AF XY:

0.00244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0358

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000383

Gnomad OTH exome

AF:

0.000453

GnomAD4 exome

AF:

0.000934

AC:

1025

AN:

1097322

Hom.:

Cov.:

AF XY:

0.000842

AC XY:

306

AN XY:

363206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26393

American (AMR)

AF:

0.00

AC:

AN:

35138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19360

East Asian (EAS)

AF:

0.0300

AC:

906

AN:

30179

South Asian (SAS)

AF:

0.000222

AC:

AN:

54138

European-Finnish (FIN)

AF:

0.0000250

AC:

AN:

39923

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000214

AC:

AN:

841979

Other (OTH)

AF:

0.00191

AC:

AN:

46076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.000881

AC:

AN:

111220

Hom.:

Cov.:

AF XY:

0.000861

AC XY:

AN XY:

33700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30529

American (AMR)

AF:

0.0000937

AC:

AN:

10673

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2617

East Asian (EAS)

AF:

0.0279

AC:

AN:

3445

South Asian (SAS)

AF:

0.000379

AC:

AN:

2639

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52852

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00127

Hom.:

ExAC

AF:

0.00255

AC:

309

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital adrenal hypoplasia, X-linked (2)

not provided (2)

not specified (2)

Congenital adrenal hypoplasia, X-linked;C1848296:46,XY sex reversal 2 (1)

NR0B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

1.3

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0038

MetaSVM

Uncertain

-0.046

MutationAssessor

Benign

1.4

PhyloP100

-1.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.030

REVEL

Benign

0.21

Sift

Benign

0.093

Sift4G

Benign

0.11

Polyphen

0.066

Vest4

0.014

MVP

0.77

MPC

0.57

ClinPred

0.0097

GERP RS

-0.90

PromoterAI

-0.0052

Neutral

(source)

Varity_R

0.044

gMVP

0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over