Genetic Variant NR0B1:p.Trp171Cys (chrX-30308851-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000475.5(NR0B1):c.513G>T(p.Trp171Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000944 in 1,059,688 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

NR0B1
NM_000475.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.348

Publications

1 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: Orphanet, Myriad Women’s Health, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR0B1	NM_000475.5 link	c.513G>T	p.Trp171Cys	missense_variant	Exon 1 of 2	ENST00000378970.5	NP_000466.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR0B1	ENST00000378970.5 link	c.513G>T	p.Trp171Cys	missense_variant	Exon 1 of 2	1	NM_000475.5	ENSP00000368253.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000600

AC:

AN:

166612

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:

0.00

Gnomad FIN exome

AF:

0.0000685

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.44e-7

AC:

AN:

1059688

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24461

American (AMR)

AF:

0.00

AC:

AN:

30237

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18173

East Asian (EAS)

AF:

0.00

AC:

AN:

26434

South Asian (SAS)

AF:

0.00

AC:

AN:

50452

European-Finnish (FIN)

AF:

0.0000257

AC:

AN:

38898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3980

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

823197

Other (OTH)

AF:

0.00

AC:

AN:

43856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.50

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.55

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

PhyloP100

-0.35

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.17

MutPred

0.67

Gain of catalytic residue at W172 (P = 0.0042);

MVP

0.90

MPC

1.9

ClinPred

0.67

GERP RS

4.4

PromoterAI

0.052

Neutral

(source)

Varity_R

0.50

gMVP

0.89

Mutation Taster

=91/9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over