chr9-124503089-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_004959.5(NR5A1):c.234G>A(p.Met78Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NR5A1
NM_004959.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.14

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: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004959.5

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 9-124503089-C-T is Pathogenic according to our data. Variant chr9-124503089-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12801.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR5A1	NM_004959.5 link	c.234G>A	p.Met78Ile	missense_variant	Exon 3 of 7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NR5A1	ENST00000373588.9 link	c.234G>A	p.Met78Ile	missense_variant	Exon 3 of 7	1	NM_004959.5	ENSP00000362690.4
NR5A1	ENST00000620110.4 link	c.234G>A	p.Met78Ile	missense_variant	Exon 3 of 6	5		ENSP00000483309.1
NR5A1	ENST00000455734.1 link	c.234G>A	p.Met78Ile	missense_variant	Exon 3 of 4	3		ENSP00000393245.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1431410

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709728

African (AFR)

AF:

0.00

AC:

AN:

32958

American (AMR)

AF:

0.00

AC:

AN:

41346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25610

East Asian (EAS)

AF:

0.00

AC:

AN:

38460

South Asian (SAS)

AF:

0.00

AC:

AN:

82384

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099410

Other (OTH)

AF:

0.00

AC:

AN:

59360

GnomAD4 genome

Cov.:

Alfa

AF:

0.00209

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

46,XY sex reversal 3

Pathogenic:1

Mar 01, 2007

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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

.;H;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

.;D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

.;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;.

Vest4

0.92

MutPred

0.94

Loss of disorder (P = 0.0371);Loss of disorder (P = 0.0371);Loss of disorder (P = 0.0371);

MVP

0.94

MPC

1.9

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.99

Mutation Taster

=3/97

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over