chrX-30304638-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000475.5(NR0B1):​c.1354A>T​(p.Ile452Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I452V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Consequence

NR0B1
NM_000475.5 missense

Scores

5
10
2

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.56
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NR0B1NM_000475.5 linkuse as main transcriptc.1354A>T p.Ile452Phe missense_variant 2/2 ENST00000378970.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NR0B1ENST00000378970.5 linkuse as main transcriptc.1354A>T p.Ile452Phe missense_variant 2/21 NM_000475.5 P1P51843-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, no assertion criteria providedresearchGharavi Laboratory, Columbia UniversitySep 16, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.76
D
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.6
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-3.0
D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.015
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.99
D
Vest4
0.49
MutPred
0.58
Loss of catalytic residue at L447 (P = 0.3404);
MVP
0.97
MPC
1.9
ClinPred
0.98
D
GERP RS
1.9
Varity_R
0.72
gMVP
0.84

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: rs1569267996; hg19: chrX-30322755; API