chrX-30308463-G-T

Variant names:

• chrX-30308463-G-T
• rs1555973010
• NM_000475.5:c.901C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.39
• Publications: 0 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000475.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR0B1	NM_000475.5	MANE Select	c.901C>A	p.Gln301Lys	missense	Exon 1 of 2	NP_000466.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR0B1	ENST00000378970.5	TSL:1 MANE Select	c.901C>A	p.Gln301Lys	missense	Exon 1 of 2	ENSP00000368253.4
	NR0B1	ENST00000378963.1	TSL:2	c.16C>A	p.Gln6Lys	missense	Exon 1 of 2	ENSP00000368246.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1086853 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 355215

African (AFR) AF: 0.00 AC: 0 AN: 26166

American (AMR) AF: 0.00 AC: 0 AN: 33696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19167

East Asian (EAS) AF: 0.00 AC: 0 AN: 29592

South Asian (SAS) AF: 0.00 AC: 0 AN: 52674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4093

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836515

Other (OTH) AF: 0.00 AC: 0 AN: 45680

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		9.4
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	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	D
GERP RS		5.3
PromoterAI		0.015	Neutral
Varity_R		0.97
gMVP		0.86
Mutation Taster		=43/57	disease causing

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: rs1555973010; hg19: chrX-30326580;