X-30304582-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000475.5(NR0B1):c.1410A>G(p.Ile470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,210,221 control chromosomes in the GnomAD database, including 2 homozygotes. There are 268 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., 36 hem., cov: 23)

Exomes 𝑓: 0.00056 ( 1 hom. 232 hem. )

Consequence

NR0B1
NM_000475.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.403

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005216688).

BP6

Variant X-30304582-T-C is Benign according to our data. Variant chrX-30304582-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1205002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-30304582-T-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR0B1	NM_000475.5 link	c.1410A>G	p.Ile470Met	missense_variant	Exon 2 of 2	ENST00000378970.5	NP_000466.2	P51843-1F1D8P4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR0B1	ENST00000378970.5 link	c.1410A>G	p.Ile470Met	missense_variant	Exon 2 of 2	1	NM_000475.5	ENSP00000368253.4		P51843-1

Frequencies

GnomAD3 genomes

AF:

0.000810

AC:

AN:

112307

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

34469

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00868

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00343

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000962

AC:

176

AN:

182944

Hom.:

AF XY:

0.000831

AC XY:

AN XY:

67410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00413

Gnomad NFE exome

AF:

0.000722

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.000560

AC:

615

AN:

1097861

Hom.:

Cov.:

AF XY:

0.000639

AC XY:

232

AN XY:

363225

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00573

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00324

Gnomad4 NFE exome

AF:

0.000409

Gnomad4 OTH exome

AF:

0.000608

GnomAD4 genome

AF:

0.000810

AC:

AN:

112360

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

34532

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00868

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00343

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000858

Hom.:

Bravo

AF:

0.000408

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.000774

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:2

Aug 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NR0B1-related disorder

Benign:1

Jan 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Nov 11, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

6.6

DANN

Benign

0.60

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.15

REVEL

Benign

0.17

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.012

Polyphen

0.092

Vest4

0.13

MVP

0.63

MPC

0.62

ClinPred

0.046

GERP RS

-7.9

Varity_R

0.19

gMVP

0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over