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

1
9
9

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]

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
NR5A1NM_004959.5 linkuse as main transcriptc.1379A>C p.Gln460Pro missense_variant 7/7 ENST00000373588.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NR5A1ENST00000373588.9 linkuse as main transcriptc.1379A>C p.Gln460Pro missense_variant 7/71 NM_004959.5 P1
NR5A1ENST00000620110.4 linkuse as main transcriptc.1259A>C p.Gln420Pro missense_variant 6/65
NR5A1ENST00000373587.3 linkuse as main transcriptc.731A>C p.Gln244Pro missense_variant 5/53

Frequencies

GnomAD3 genomes
AF:
0.000108
AC:
14
AN:
129820
Hom.:
0
Cov.:
29
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:
19
AN:
174450
Hom.:
0
AF XY:
0.000139
AC XY:
13
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.:
0
Cov.:
38
AF XY:
0.000158
AC XY:
91
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:
14
AN:
129868
Hom.:
0
Cov.:
29
AF XY:
0.0000976
AC XY:
6
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.:
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
LINK: link

Submissions by phenotype

Oligosynaptic infertility;C2751824:46,XY disorder of sex development Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 10, 2023This 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 submitterin vitro;researchInstitute of Reproductive Genetics, University of MünsterJan 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
DEOGEN2
Uncertain
0.68
.;D;.
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
MutationAssessor
Benign
0.0
.;N;.
MutationTaster
Benign
0.96
D
PrimateAI
Uncertain
0.58
T
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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146454575; hg19: chr9-127245044; API