rs775441984

Variant names:

• chr9-124503172-C-A
• rs775441984
• NM_004959.5:c.151G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-124503172-C-A
• chr9-124503172-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004959.5(NR5A1):​c.151G>T​(p.Glu51*) variant causes a stop gained change. 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NR5A1 NM_004959.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.97
• Publications: 1 publications found

Genes affected

NR5A1 (HGNC:7983): (nuclear receptor subfamily 5 group A member 1) The protein encoded by this gene is a transcriptional activator involved in sex determination. The encoded protein binds DNA as a monomer. Defects in this gene are a cause of XY sex reversal with or without adrenal failure as well as adrenocortical insufficiency without ovarian defect. [provided by RefSeq, Jul 2008]

NR5A1 Gene-Disease associations (from GenCC):

• 46,XX sex reversal 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46,XY sex reversal 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• premature ovarian failure 7

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XX ovotesticular disorder of sex development

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XX sex reversal 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-124503172-C-A is Pathogenic according to our data. Variant chr9-124503172-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 216975.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004959.5. 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
	NR5A1	NM_004959.5	MANE Select	c.151G>T	p.Glu51*	stop_gained	Exon 3 of 7	NP_004950.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR5A1	ENST00000373588.9	TSL:1 MANE Select	c.151G>T	p.Glu51*	stop_gained	Exon 3 of 7	ENSP00000362690.4
	NR5A1	ENST00000620110.4	TSL:5	c.151G>T	p.Glu51*	stop_gained	Exon 3 of 6	ENSP00000483309.1
	NR5A1	ENST00000455734.1	TSL:3	c.151G>T	p.Glu51*	stop_gained	Exon 3 of 4	ENSP00000393245.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448232 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719388

African (AFR) AF: 0.00 AC: 0 AN: 33160

American (AMR) AF: 0.00 AC: 0 AN: 43424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39142

South Asian (SAS) AF: 0.00 AC: 0 AN: 84104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106498

Other (OTH) AF: 0.00 AC: 0 AN: 59876

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 3 Pathogenic:1

Jul 29, 2014

UCLA Clinical Genomics Center, UCLA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		6.0
Vest4		0.79
GERP RS		4.6
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs775441984; hg19: chr9-127265451;