chrX-30304673-T-A

Variant names:

• chrX-30304673-T-A
• rs28935481
• NM_000475.5:c.1319A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000475.5(NR0B1):​c.1319A>T​(p.Asn440Ile) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N440S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NR0B1 NM_000475.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.629
• Publications: 6 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-30304673-T-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR0B1	NM_000475.5	c.1319A>T	p.Asn440Ile	missense_variant	Exon 2 of 2	ENST00000378970.5	NP_000466.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR0B1	ENST00000378970.5	c.1319A>T	p.Asn440Ile	missense_variant	Exon 2 of 2	1	NM_000475.5	ENSP00000368253.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital adrenal hypoplasia, X-linked Pathogenic:1

Jul 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.63
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.020	D
Polyphen		0.97	D
Vest4		0.83
MutPred		0.88		Loss of catalytic residue at N440 (P = 0.1579);
MVP		0.98
MPC		1.7
ClinPred		0.98	D
GERP RS		-1.6
Varity_R		0.66
gMVP		0.82
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28935481; hg19: chrX-30322790;