NM_000475.5:c.1319A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM5BP4_Moderate

The NM_000475.5(NR0B1):​c.1319A>G​(p.Asn440Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,616 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 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. N440I) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

NR0B1
NM_000475.5 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.629

Publications

6 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-30304673-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10957.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.17064038).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NR0B1NM_000475.5 linkc.1319A>G p.Asn440Ser 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
NR0B1ENST00000378970.5 linkc.1319A>G p.Asn440Ser missense_variant Exon 2 of 2 1 NM_000475.5 ENSP00000368253.4 P51843-1

Frequencies

GnomAD3 genomes
AF:
0.00000900
AC:
1
AN:
111066
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000168
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000545
AC:
1
AN:
183517
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:
0.0000625
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1097550
Hom.:
0
Cov.:
29
AF XY:
0.00000276
AC XY:
1
AN XY:
362910
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26392
American (AMR)
AF:
0.00
AC:
0
AN:
35207
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19384
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54137
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40528
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4134
European-Non Finnish (NFE)
AF:
0.00000238
AC:
2
AN:
841489
Other (OTH)
AF:
0.00
AC:
0
AN:
46077
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000900
AC:
1
AN:
111066
Hom.:
0
Cov.:
23
AF XY:
0.0000301
AC XY:
1
AN XY:
33268
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30435
American (AMR)
AF:
0.00
AC:
0
AN:
10405
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2639
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3572
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2574
European-Finnish (FIN)
AF:
0.000168
AC:
1
AN:
5957
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
240
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
53060
Other (OTH)
AF:
0.00
AC:
0
AN:
1499
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 25, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: NR0B1 c.1319A>G (p.Asn440Ser) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-06 in 183517 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1319A>G in individuals affected with X-Linked Adrenal Hypoplasia Congenita and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
10
DANN
Benign
0.83
DEOGEN2
Uncertain
0.59
D
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.78
T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.17
T
MetaSVM
Uncertain
-0.074
T
MutationAssessor
Benign
0.51
N
PhyloP100
0.63
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.24
Sift
Benign
0.46
T
Sift4G
Benign
0.41
T
Polyphen
0.022
B
Vest4
0.066
MutPred
0.64
Loss of catalytic residue at N440 (P = 0.256);
MVP
0.71
MPC
0.50
ClinPred
0.044
T
GERP RS
-1.6
Varity_R
0.068
gMVP
0.42
Mutation Taster
=92/8
polymorphism

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

Other links and lift over

dbSNP: rs28935481; hg19: chrX-30322790; API