X-30308866-C-T

Variant names:

• chrX-30308866-C-T
• rs2269345
• NM_000475.5:c.498G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000475.5(NR0B1):​c.498G>A​(p.Arg166Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,204,414 control chromosomes in the GnomAD database, including 30,177 homozygotes. There are 100,218 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (4242 hom., 9254 hem., cov: 23)
  • Exomes 𝑓: 0.24 (25935 hom. 90964 hem.)
• Consequence: NR0B1 NM_000475.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.477
• Publications: 19 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-30308866-C-T is Benign according to our data. Variant chrX-30308866-C-T is described in ClinVar as Benign. ClinVar VariationId is 256225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.477 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

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.498G>A	p.Arg166Arg	synonymous	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.498G>A	p.Arg166Arg	synonymous	Exon 1 of 2	ENSP00000368253.4

Frequencies

GnomAD3 genomes AF: 0.296 AC: 32511 AN: 109841 Hom.: 4241 Cov.: 23

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.0775

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.334 AC: 56300 AN: 168478 AF XY: 0.330

Gnomad AFR exome AF: 0.452

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.292

Gnomad EAS exome AF: 0.725

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.244 AC: 266596 AN: 1094516 Hom.: 25935 Cov.: 36 AF XY: 0.252 AC XY: 90964 AN XY: 360844

African (AFR) AF: 0.437 AC: 11532 AN: 26364

American (AMR) AF: 0.435 AC: 15096 AN: 34730

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 5490 AN: 19332

East Asian (EAS) AF: 0.670 AC: 20163 AN: 30098

South Asian (SAS) AF: 0.523 AC: 28168 AN: 53871

European-Finnish (FIN) AF: 0.189 AC: 7449 AN: 39428

Middle Eastern (MID) AF: 0.282 AC: 1161 AN: 4113

European-Non Finnish (NFE) AF: 0.195 AC: 164169 AN: 840609

Other (OTH) AF: 0.291 AC: 13368 AN: 45971

GnomAD4 genome AF: 0.296 AC: 32552 AN: 109898 Hom.: 4242 Cov.: 23 AF XY: 0.286 AC XY: 9254 AN XY: 32366

African (AFR) AF: 0.429 AC: 12897 AN: 30076

American (AMR) AF: 0.343 AC: 3623 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 717 AN: 2614

East Asian (EAS) AF: 0.705 AC: 2361 AN: 3348

South Asian (SAS) AF: 0.550 AC: 1362 AN: 2478

European-Finnish (FIN) AF: 0.161 AC: 951 AN: 5906

Middle Eastern (MID) AF: 0.264 AC: 56 AN: 212

European-Non Finnish (NFE) AF: 0.192 AC: 10109 AN: 52531

Other (OTH) AF: 0.280 AC: 424 AN: 1513

Alfa AF: 0.251 Hom.: 2773

Bravo AF: 0.326

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Aug 01, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Congenital adrenal hypoplasia, X-linked Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital adrenal hypoplasia, X-linked;C1848296:46,XY sex reversal 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.0
DANN	Benign	0.90
PhyloP100		0.48
PromoterAI		-0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2269345; hg19: chrX-30326983; COSMIC: COSV66764241; COSMIC: COSV66764241;