Genetic Variant NR0B1:p.Gln301Lys (chrX-30308463-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000475.5(NR0B1):c.901C>A(p.Gln301Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

NR0B1
NM_000475.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.39

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: 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR0B1	NM_000475.5 link	c.901C>A	p.Gln301Lys	missense_variant	Exon 1 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.901C>A	p.Gln301Lys	missense_variant	Exon 1 of 2	1	NM_000475.5	ENSP00000368253.4		P51843-1
NR0B1	ENST00000378963.1 link	c.16C>A	p.Gln6Lys	missense_variant	Exon 1 of 2	2		ENSP00000368246.1		A6NNU8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1086853

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

355215

African (AFR)

AF:

0.00

AC:

AN:

26166

American (AMR)

AF:

0.00

AC:

AN:

33696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19167

East Asian (EAS)

AF:

0.00

AC:

AN:

29592

South Asian (SAS)

AF:

0.00

AC:

AN:

52674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4093

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836515

Other (OTH)

AF:

0.00

AC:

AN:

45680

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.71

BayesDel_noAF

Pathogenic

0.78

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;.

PhyloP100

9.4

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.88

MutPred

0.84

Gain of ubiquitination at Q301 (P = 0.0289);.;

MVP

1.0

MPC

1.7

ClinPred

1.0

GERP RS

5.3

PromoterAI

0.015

Neutral

(source)

Varity_R

0.97

gMVP

0.86

Mutation Taster

=43/57

disease causing

(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