rs1057517779

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_004959.5(NR5A1):c.937C>T(p.Arg313Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R313H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NR5A1
NM_004959.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.96

Publications

13 publications found

Variant links:

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)

NR5A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-124493082-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.3359 (below the threshold of 3.09). Trascript score misZ: 2.4094 (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XY sex reversal 3, 46,XX sex reversal 4, 46,XX ovotesticular disorder of sex development, premature ovarian failure 7, spermatogenic failure 8, 46,XY partial gonadal dysgenesis, 46 XX gonadal dysgenesis, male infertility with azoospermia or oligozoospermia due to single gene mutation, 46,XX sex reversal 1, 46,XY complete gonadal dysgenesis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 9-124493083-G-A is Pathogenic according to our data. Variant chr9-124493083-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR5A1	NM_004959.5 link	c.937C>T	p.Arg313Cys	missense_variant	Exon 5 of 7	ENST00000373588.9	NP_004950.2	Q13285F1D8R8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR5A1	ENST00000373588.9 link	c.937C>T	p.Arg313Cys	missense_variant	Exon 5 of 7	1	NM_004959.5	ENSP00000362690.4	Q13285
NR5A1	ENST00000373587.3 link	c.289C>T	p.Arg97Cys	missense_variant	Exon 3 of 5	3		ENSP00000362689.3	Q5T6F7
NR5A1	ENST00000620110.4 link	c.871-1855C>T		intron_variant	Intron 4 of 5	5		ENSP00000483309.1	F1DAM0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459002

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725622

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

85882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111424

Other (OTH)

AF:

0.00

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Genetic non-acquired premature ovarian failure

Pathogenic:1

Oct 01, 2019

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Oligosynaptic infertility;C2751824:46,XY disorder of sex development

Pathogenic:1

Apr 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NR5A1 function (PMID: 22028768, 25122490, 27169744). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372437). This missense change has been observed in individual(s) with autosomal dominant disorders of sex development (DSD) (PMID: 25122490, 27169744, 30425642). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 313 of the NR5A1 protein (p.Arg313Cys). -

not provided

Pathogenic:1

Aug 16, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate reduced transactivation activity on CYP11A1 and CYP17A1 promoters (Allali et al., 2011; Malikova et al., 2014); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25122490, 27169744, 30425642, 30067310, 25383892, 32369823, 22028768) -

46,XY sex reversal 3

Pathogenic:1

Nov 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

2.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.87

MutPred

0.83

Loss of disorder (P = 0.0397);.;

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

3.5

Varity_R

0.94

gMVP

0.69

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over