Genetic Variant NR0B1:p.Ile452Val (chrX-30304638-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000475.5(NR0B1):c.1354A>G(p.Ile452Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,774 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I452F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

NR0B1
NM_000475.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.56

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000475.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18913206).

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.1354A>G	p.Ile452Val	missense	Exon 2 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.1354A>G	p.Ile452Val	missense	Exon 2 of 2	ENSP00000368253.4	P51843-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26370

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

54115

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

840795

Other (OTH)

AF:

0.00

AC:

AN:

46054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital adrenal hypoplasia, X-linked (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0089

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.75

M_CAP

Benign

0.079

MetaRNN

Benign

0.19

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.1

PhyloP100

1.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.21

REVEL

Uncertain

0.33

Sift

Benign

0.16

Sift4G

Benign

0.40

Polyphen

0.053

Vest4

0.11

MutPred

0.57

Gain of helix (P = 0.2059)

MVP

0.80

MPC

0.55

ClinPred

0.31

GERP RS

1.9

Varity_R

0.087

gMVP

0.40

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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