rs201095702

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP2PP5BP4BS2_Supporting

The NM_004959.5(NR5A1):c.634G>A(p.Gly212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,558,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

NR5A1
NM_004959.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.0860

Publications

7 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: Uncertain_significance. The variant received 0 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,XY complete gonadal dysgenesis, 46,XX ovotesticular disorder of sex development, premature ovarian failure 7, 46,XX sex reversal 4, spermatogenic failure 8, 46 XX gonadal dysgenesis, 46,XX sex reversal 1, male infertility with azoospermia or oligozoospermia due to single gene mutation, 46,XY partial gonadal dysgenesis.

PP5

Variant 9-124500326-C-T is Pathogenic according to our data. Variant chr9-124500326-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29895.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.05786687). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004959.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR5A1	NM_004959.5	MANE Select	c.634G>A	p.Gly212Ser	missense	Exon 4 of 7	NP_004950.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR5A1	ENST00000373588.9	TSL:1 MANE Select	c.634G>A	p.Gly212Ser	missense	Exon 4 of 7	ENSP00000362690.4	Q13285
NR5A1	ENST00000950385.1		c.634G>A	p.Gly212Ser	missense	Exon 4 of 7	ENSP00000620444.1
NR5A1	ENST00000911688.1		c.634G>A	p.Gly212Ser	missense	Exon 4 of 7	ENSP00000581746.1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000133

AC:

AN:

158206

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00161

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000330

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1405766

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

694180

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31936

American (AMR)

AF:

0.00

AC:

AN:

36400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25240

East Asian (EAS)

AF:

0.000552

AC:

AN:

36230

South Asian (SAS)

AF:

0.00

AC:

AN:

80232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

1083330

Other (OTH)

AF:

0.0000515

AC:

AN:

58268

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

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:

0.0000722

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41582

American (AMR)

AF:

0.0000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.0000868

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000236

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000884

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spermatogenic failure 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.090

CADD

Benign

7.0

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.28

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.66

M_CAP

Benign

0.056

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.0

PhyloP100

-0.086

PrimateAI

Benign

0.40

PROVEAN

Benign

0.64

REVEL

Uncertain

0.57

Sift

Benign

1.0

Sift4G

Benign

0.93

Polyphen

0.0

Vest4

0.66

MVP

0.98

MPC

0.74

ClinPred

0.0061

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.38

Mutation Taster

=40/60

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over