chrX-30309250-G-A

Variant names:

• chrX-30309250-G-A
• rs6150
• NM_000475.5:c.114C>T

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.114C>T​(p.Cys38Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,205,518 control chromosomes in the GnomAD database, including 14,961 homozygotes. There are 71,232 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1053 hom., 4649 hem., cov: 24)
  • Exomes 𝑓: 0.19 (13908 hom. 66583 hem.)
• Consequence: NR0B1 NM_000475.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.978
• Publications: 11 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health
• 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=-0.64).
• BP6: Variant X-30309250-G-A is Benign according to our data. Variant chrX-30309250-G-A is described in ClinVar as Benign. ClinVar VariationId is 256224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.978 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR0B1	NM_000475.5	MANE Select	c.114C>T	p.Cys38Cys	synonymous	Exon 1 of 2	NP_000466.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR0B1	ENST00000378970.5	TSL:1 MANE Select	c.114C>T	p.Cys38Cys	synonymous	Exon 1 of 2	ENSP00000368253.4	P51843-1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 15982 AN: 111370 Hom.: 1053 Cov.: 24

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.0754

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.129

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.151 AC: 25469 AN: 168948 AF XY: 0.149

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.0544

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.187 AC: 204878 AN: 1094096 Hom.: 13908 Cov.: 35 AF XY: 0.185 AC XY: 66583 AN XY: 360502

African (AFR) AF: 0.0399 AC: 1051 AN: 26356

American (AMR) AF: 0.0602 AC: 2106 AN: 34970

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 4300 AN: 19293

East Asian (EAS) AF: 0.129 AC: 3892 AN: 30090

South Asian (SAS) AF: 0.0921 AC: 4956 AN: 53830

European-Finnish (FIN) AF: 0.258 AC: 10121 AN: 39231

Middle Eastern (MID) AF: 0.132 AC: 545 AN: 4126

European-Non Finnish (NFE) AF: 0.202 AC: 169823 AN: 840306

Other (OTH) AF: 0.176 AC: 8084 AN: 45894

GnomAD4 genome AF: 0.144 AC: 15990 AN: 111422 Hom.: 1053 Cov.: 24 AF XY: 0.138 AC XY: 4649 AN XY: 33794

African (AFR) AF: 0.0397 AC: 1227 AN: 30872

American (AMR) AF: 0.102 AC: 1088 AN: 10687

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 577 AN: 2640

East Asian (EAS) AF: 0.123 AC: 426 AN: 3459

South Asian (SAS) AF: 0.0761 AC: 204 AN: 2681

European-Finnish (FIN) AF: 0.248 AC: 1461 AN: 5903

Middle Eastern (MID) AF: 0.128 AC: 27 AN: 211

European-Non Finnish (NFE) AF: 0.200 AC: 10560 AN: 52772

Other (OTH) AF: 0.134 AC: 205 AN: 1529

Alfa AF: 0.185 Hom.: 2157

Bravo AF: 0.131

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital adrenal hypoplasia, X-linked (1)
-	-	1	Congenital adrenal hypoplasia, X-linked;C1848296:46,XY sex reversal 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.6
DANN	Benign	0.80
PhyloP100		0.98
PromoterAI		0.029	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: rs6150; hg19: chrX-30327367; COSMIC: COSV66764107; COSMIC: COSV66764107;