9-124482765-T-G

Position:

chr9-124482765-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_004959.5(NR5A1):c.1379A>C(p.Gln460Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,298,462 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q460R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NR5A1
NM_004959.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.11

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a region_of_interest Important for dimerization (size 231) in uniprot entity STF1_HUMAN there are 48 pathogenic changes around while only 0 benign (100%) in NM_004959.5

BP4

Computational evidence support a benign effect (MetaRNN=0.12625375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR5A1	NM_004959.5 linkuse as main transcript	c.1379A>C	p.Gln460Pro	missense_variant	7/7	ENST00000373588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NR5A1	ENST00000373588.9 linkuse as main transcript	c.1379A>C	p.Gln460Pro	missense_variant	7/7	1	NM_004959.5	P1
NR5A1	ENST00000620110.4 linkuse as main transcript	c.1259A>C	p.Gln420Pro	missense_variant	6/6	5
NR5A1	ENST00000373587.3 linkuse as main transcript	c.731A>C	p.Gln244Pro	missense_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

129820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000263

Gnomad SAS

AF:

0.000272

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000127

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

174450

Hom.:

AF XY:

0.000139

AC XY:

AN XY:

93254

show subpopulations

Gnomad AFR exome

AF:

0.000293

Gnomad AMR exome

AF:

0.000114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000782

Gnomad SAS exome

AF:

0.000204

Gnomad FIN exome

AF:

0.0000618

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.000208

GnomAD4 exome

AF:

0.000149

AC:

174

AN:

1168594

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

574570

show subpopulations

Gnomad4 AFR exome

AF:

0.000156

Gnomad4 AMR exome

AF:

0.000101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00107

Gnomad4 SAS exome

AF:

0.0000766

Gnomad4 FIN exome

AF:

0.000138

Gnomad4 NFE exome

AF:

0.000145

Gnomad4 OTH exome

AF:

0.000165

GnomAD4 genome

AF:

0.000108

AC:

AN:

129868

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

61470

show subpopulations

Gnomad4 AFR

AF:

0.000115

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000263

Gnomad4 SAS

AF:

0.000272

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000127

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000287

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000837

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 460 of the NR5A1 protein (p.Gln460Pro). This variant is present in population databases (rs146454575, gnomAD 0.02%). This missense change has been observed in individual(s) with 46XY sex reversal (Invitae). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. This variant disrupts the p.Gln460 amino acid residue in NR5A1. Other variant(s) that disrupt this residue have been observed in individuals with NR5A1-related conditions (PMID: 29935645; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Male infertility

Uncertain:1

Uncertain significance, criteria provided, single submitter

in vitro;research

Institute of Reproductive Genetics, University of Münster

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

.;D;.

Eigen

Benign

-0.082

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.76

T;T;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.0

.;N;.

MutationTaster

Benign

0.96

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.3

.;N;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.49

.;P;.

Vest4

0.19

MVP

0.81

MPC

0.90

ClinPred

0.071

GERP RS

3.7

Varity_R

0.91

gMVP

0.26

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