rs1057517779

chr9-124493083-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004959.5(NR5A1):c.937C>T(p.Arg313Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R313H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.96

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain NR LBD (size 237) in uniprot entity STF1_HUMAN there are 48 pathogenic changes around while only 0 benign (100%) in NM_004959.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-124493082-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 9-124493083-G-A is Pathogenic according to our data. Variant chr9-124493083-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-124493083-G-A is described in Lovd as [Pathogenic]. Variant chr9-124493083-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR5A1	NM_004959.5	c.937C>T	p.Arg313Cys	missense_variant	5/7	ENST00000373588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR5A1	ENST00000373588.9	c.937C>T	p.Arg313Cys	missense_variant	5/7	1	NM_004959.5	P1
NR5A1	ENST00000373587.3	c.289C>T	p.Arg97Cys	missense_variant	3/5	3
NR5A1	ENST00000620110.4	c.871-1855C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459002 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 313 of the NR5A1 protein (p.Arg313Cys). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372437). This missense change has been observed in individual(s) with autosomal dominant disorders of sex development (DSD) (PMID: 25122490, 27169744, 30425642). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NR5A1 function (PMID: 22028768, 25122490, 27169744). -

Genetic non-acquired premature ovarian failure Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Oct 01, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2022

Published functional studies demonstrate reduced transactivation activity on CYP11A1 and CYP17A1 promoters (Allali et al., 2011; Malikova et al., 2014); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25122490, 27169744, 30425642, 30067310, 25383892, 32369823, 22028768) -

46,XY sex reversal 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.83		Loss of disorder (P = 0.0397);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.94
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1057517779; hg19: chr9-127255362;