rs387906690

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP2PP5BP4BS2

The NM_004959.5(NR5A1):c.392C>T(p.Pro131Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,611,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P131P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

NR5A1
NM_004959.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.39

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: Likely_benign. The variant received -3 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.

PP5

Variant 9-124500568-G-A is Pathogenic according to our data. Variant chr9-124500568-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29894.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.14478266). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR5A1	NM_004959.5 link	c.392C>T	p.Pro131Leu	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.392C>T	p.Pro131Leu	missense_variant	Exon 4 of 7	1	NM_004959.5	ENSP00000362690.4	Q13285
NR5A1	ENST00000620110.4 link	c.392C>T	p.Pro131Leu	missense_variant	Exon 4 of 6	5		ENSP00000483309.1	F1DAM0
NR5A1	ENST00000455734.1 link	c.392C>T	p.Pro131Leu	missense_variant	Exon 4 of 4	3		ENSP00000393245.1	Q5T6F6
NR5A1	ENST00000373587.3 link	c.40-296C>T		intron_variant	Intron 1 of 4	3		ENSP00000362689.3	Q5T6F7

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000625

AC:

AN:

240146

AF XY:

0.0000530

show subpopulations

Gnomad AFR exome

AF:

0.0000682

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000939

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1459342

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.0000224

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000220

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111850

Other (OTH)

AF:

0.0000166

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000497

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spermatogenic failure 8

Pathogenic:1

Oct 08, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.41

.;T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.1

.;L;.

PhyloP100

3.4

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.70

.;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.32

.;T;T

Sift4G

Benign

0.78

T;T;.

Polyphen

0.0020

.;B;.

Vest4

0.79

MutPred

0.41

Loss of glycosylation at P131 (P = 0.0031);Loss of glycosylation at P131 (P = 0.0031);Loss of glycosylation at P131 (P = 0.0031);

MVP

1.0

MPC

0.87

ClinPred

0.057

GERP RS

3.8

PromoterAI

-0.0012

Neutral

(source)

Varity_R

0.060

gMVP

0.15

Mutation Taster

=37/63

disease causing (ClinVar)

(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