9-124500585-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004959.5(NR5A1):c.375G>A(p.Pro125Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,611,976 control chromosomes in the GnomAD database, including 3,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 1801 hom., cov: 33)

Exomes 𝑓: 0.0088 ( 1681 hom. )

Consequence

NR5A1
NM_004959.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.56

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 9-124500585-C-T is Benign according to our data. Variant chr9-124500585-C-T is described in ClinVar as Benign. ClinVar VariationId is 259590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR5A1	NM_004959.5 link	c.375G>A	p.Pro125Pro	synonymous_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.375G>A	p.Pro125Pro	synonymous_variant	Exon 4 of 7	1	NM_004959.5	ENSP00000362690.4	Q13285
NR5A1	ENST00000620110.4 link	c.375G>A	p.Pro125Pro	synonymous_variant	Exon 4 of 6	5		ENSP00000483309.1	F1DAM0
NR5A1	ENST00000455734.1 link	c.375G>A	p.Pro125Pro	synonymous_variant	Exon 4 of 4	3		ENSP00000393245.1	Q5T6F6
NR5A1	ENST00000373587.3 link	c.40-313G>A		intron_variant	Intron 1 of 4	3		ENSP00000362689.3	Q5T6F7

Frequencies

GnomAD3 genomes

AF:

0.0843

AC:

12824

AN:

152146

Hom.:

1800

Cov.:

show subpopulations

Gnomad AFR

AF:

0.293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0313

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.0654

GnomAD2 exomes

AF:

0.0216

AC:

5183

AN:

240292

AF XY:

0.0165

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.000815

Gnomad EAS exome

AF:

0.00146

Gnomad FIN exome

AF:

0.0000482

Gnomad NFE exome

AF:

0.000844

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.00877

AC:

12796

AN:

1459712

Hom.:

1681

Cov.:

AF XY:

0.00759

AC XY:

5509

AN XY:

726150

show subpopulations

African (AFR)

AF:

0.304

AC:

10176

AN:

33472

American (AMR)

AF:

0.0150

AC:

670

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26126

East Asian (EAS)

AF:

0.000806

AC:

AN:

39694

South Asian (SAS)

AF:

0.000707

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.000116

AC:

AN:

51596

Middle Eastern (MID)

AF:

0.0134

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.000597

AC:

664

AN:

1111860

Other (OTH)

AF:

0.0183

AC:

1102

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

661

1322

1984

2645

3306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.0844

AC:

12846

AN:

152264

Hom.:

1801

Cov.:

AF XY:

0.0807

AC XY:

6009

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.292

AC:

12149

AN:

41538

American (AMR)

AF:

0.0312

AC:

477

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

67996

Other (OTH)

AF:

0.0647

AC:

137

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

487

974

1461

1948

2435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0111

Hom.:

Bravo

AF:

0.0964

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31787151) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.025

(source)

DANN

Benign

0.70

PhyloP100

-2.6

PromoterAI

0.011

Neutral

(source)

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