9-124482765-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.11

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]

ACMG classification

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 47 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	c.1379A>C	p.Gln460Pro	missense_variant	7/7	ENST00000373588.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 14 AN: 129820 Hom.: 0 Cov.: 29

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: 19 AN: 174450 Hom.: 0 AF XY: 0.000139 AC XY: 13 AN XY: 93254

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.: 0 Cov.: 38 AF XY: 0.000158 AC XY: 91 AN XY: 574570

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: 14 AN: 129868 Hom.: 0 Cov.: 29 AF XY: 0.0000976 AC XY: 6 AN XY: 61470

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.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000837 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oligosynaptic infertility;C2751824:46,XY disorder of sex development Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	-0.082
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.58	T
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.49	.;P;.
Vest4		0.19
MVP		0.81
MPC		0.90
ClinPred		0.071	T
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

Other links and lift over

dbSNP: rs146454575; hg19: chr9-127245044;