chrX-30304582-T-C

Variant summary

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

The NM_000475.5(NR0B1):ā€‹c.1410A>Gā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00081 ( 1 hom., 36 hem., cov: 23)
Exomes š‘“: 0.00056 ( 1 hom. 232 hem. )

Consequence

NR0B1
NM_000475.5 missense

Scores

4
13

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]

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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/exons MANE UniProt
NR0B1NM_000475.5 linkuse as main transcriptc.1410A>G p.Ile470Met missense_variant 2/2 ENST00000378970.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NR0B1ENST00000378970.5 linkuse as main transcriptc.1410A>G p.Ile470Met missense_variant 2/21 NM_000475.5 P1P51843-1

Frequencies

GnomAD3 genomes
AF:
0.000810
AC:
91
AN:
112307
Hom.:
1
Cov.:
23
AF XY:
0.00104
AC XY:
36
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.:
0
AF XY:
0.000831
AC XY:
56
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.:
1
Cov.:
30
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:
91
AN:
112360
Hom.:
1
Cov.:
23
AF XY:
0.00104
AC XY:
36
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.:
41
Bravo
AF:
0.000408
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00119
AC:
8
ExAC
AF:
0.000774
AC:
94
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
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 15, 2021- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -
NR0B1-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 02, 2020This 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
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 11, 2019In 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
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
6.6
DANN
Benign
0.60
DEOGEN2
Benign
0.23
T
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.58
T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.0052
T
MetaSVM
Benign
-0.46
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.15
N
REVEL
Benign
0.17
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.012
D
Polyphen
0.092
B
Vest4
0.13
MVP
0.63
MPC
0.62
ClinPred
0.046
T
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.

Other links and lift over

dbSNP: rs151317312; hg19: chrX-30322699; API