9-124500523-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 259591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-124500523-C-G is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.101

AC:

23547

AN:

233592

Hom.:

5458

AF XY:

0.0877

AC XY:

11313

AN XY:

129032

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 SAS exome

AF:

0.0861

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

Gnomad4 AFR exome

AF:

0.771

Gnomad4 AMR exome

AF:

0.0679

Gnomad4 ASJ exome

AF:

0.0234

Gnomad4 EAS exome

AF:

0.303

Gnomad4 SAS exome

AF:

0.0858

Gnomad4 FIN exome

AF:

0.00712

Gnomad4 NFE exome

AF:

0.0108

Gnomad4 OTH exome

AF:

0.0841

GnomAD4 genome

AF:

0.236

AC:

35886

AN:

152180

Hom.:

12009

Cov.:

AF XY:

0.232

AC XY:

17273

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.740

Gnomad4 AMR

AF:

0.107

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.325

Gnomad4 SAS

AF:

0.108

Gnomad4 FIN

AF:

0.00423

Gnomad4 NFE

AF:

0.0123

Gnomad4 OTH

AF:

0.181

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

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;.

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

Varity_R

0.038

gMVP

0.19

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over