9-124500523-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004959.5(NR5A1):c.437G>C(p.Gly146Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 1,607,478 control chromosomes in the GnomAD database, including 25,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 12009 hom., cov: 33)

Exomes 𝑓: 0.046 ( 13192 hom. )

Consequence

NR5A1
NM_004959.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0130

Publications

54 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: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=8.3544745E-7).

BP6

Variant 9-124500523-C-G is Benign according to our data. Variant chr9-124500523-C-G is described in ClinVar as Benign. ClinVar VariationId is 259591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR5A1	NM_004959.5 link	c.437G>C	p.Gly146Ala	missense_variant	Exon 4 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.437G>C	p.Gly146Ala	missense_variant	Exon 4 of 7	1	NM_004959.5	ENSP00000362690.4	Q13285
NR5A1	ENST00000620110.4 link	c.437G>C	p.Gly146Ala	missense_variant	Exon 4 of 6	5		ENSP00000483309.1	F1DAM0
NR5A1	ENST00000455734.1 link	c.437G>C	p.Gly146Ala	missense_variant	Exon 4 of 4	3		ENSP00000393245.1	Q5T6F6
NR5A1	ENST00000373587.3 link	c.40-251G>C		intron_variant	Intron 1 of 4	3		ENSP00000362689.3	Q5T6F7

Frequencies

GnomAD3 genomes

AF:

0.235

AC:

35784

AN:

152062

Hom.:

11965

Cov.:

show subpopulations

Gnomad AFR

AF:

0.739

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.325

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.00423

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.182

GnomAD2 exomes

AF:

0.101

AC:

23547

AN:

233592

AF XY:

0.0877

show subpopulations

Gnomad AFR exome

AF:

0.764

Gnomad AMR exome

AF:

0.0626

Gnomad ASJ exome

AF:

0.0243

Gnomad EAS exome

AF:

0.348

Gnomad FIN exome

AF:

0.00578

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.0623

GnomAD4 exome

AF:

0.0458

AC:

66704

AN:

1455298

Hom.:

13192

Cov.:

AF XY:

0.0442

AC XY:

32004

AN XY:

724016

show subpopulations

African (AFR)

AF:

0.771

AC:

25769

AN:

33436

American (AMR)

AF:

0.0679

AC:

3028

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

609

AN:

26052

East Asian (EAS)

AF:

0.303

AC:

12015

AN:

39620

South Asian (SAS)

AF:

0.0858

AC:

7384

AN:

86100

European-Finnish (FIN)

AF:

0.00712

AC:

346

AN:

48580

Middle Eastern (MID)

AF:

0.0788

AC:

448

AN:

5688

European-Non Finnish (NFE)

AF:

0.0108

AC:

12039

AN:

1111044

Other (OTH)

AF:

0.0841

AC:

5066

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2931

5861

8792

11722

14653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1052

2104

3156

4208

5260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.236

AC:

35886

AN:

152180

Hom.:

12009

Cov.:

AF XY:

0.232

AC XY:

17273

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.740

AC:

30695

AN:

41492

American (AMR)

AF:

0.107

AC:

1633

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3470

East Asian (EAS)

AF:

0.325

AC:

1677

AN:

5156

South Asian (SAS)

AF:

0.108

AC:

520

AN:

4824

European-Finnish (FIN)

AF:

0.00423

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

837

AN:

67990

Other (OTH)

AF:

0.181

AC:

383

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

617

1234

1851

2468

3085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0761

Hom.:

964

Bravo

AF:

0.266

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.695

AC:

3016

ESP6500EA

AF:

0.0153

AC:

130

ExAC

AF:

0.109

AC:

13098

Asia WGS

AF:

0.234

AC:

811

AN:

3478

EpiCase

AF:

0.0135

EpiControl

AF:

0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31787151, 14623279, 23154282, 24434652, 23096908, 22951804, 23153500, 16500365, 16127213, 16564598, 22909003, 21691958) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

46,XY disorder of sex development

Benign:1

Jun 13, 2024

Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.30

CADD

Benign

8.4

(source)

DANN

Benign

0.068

DEOGEN2

Benign

0.29

.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.19

T;T;T

MetaRNN

Benign

8.4e-7

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.2

.;N;.

PhyloP100

0.013

PrimateAI

Benign

0.43

PROVEAN

Benign

1.5

.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.86

.;T;T

Sift4G

Benign

0.80

T;T;.

Polyphen

0.0

.;B;.

Vest4

0.072

MPC

0.80

ClinPred

0.000019

GERP RS

-0.61

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.038

gMVP

0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over