9-124500686-G-A

Position:

• chr9-124500686-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_004959.5(NR5A1):​c.274C>T​(p.Arg92Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 2.60

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-124500685-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• PP5: Variant 9-124500686-G-A is Pathogenic according to our data. Variant chr9-124500686-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265792.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.274C>T	p.Arg92Trp	missense_variant	4/7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR5A1	ENST00000373588.9	c.274C>T	p.Arg92Trp	missense_variant	4/7	1	NM_004959.5	ENSP00000362690.4
NR5A1	ENST00000620110.4	c.274C>T	p.Arg92Trp	missense_variant	4/6	5		ENSP00000483309.1
NR5A1	ENST00000455734.1	c.274C>T	p.Arg92Trp	missense_variant	4/4	3		ENSP00000393245.1
NR5A1	ENST00000373587.3	c.39+262C>T		intron_variant		3		ENSP00000362689.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28033660, 27855412, 30425642, 29393271, 32271476, 27378692, 27610946, 27490115, 30350900, 27833742, 30739115) -

46,XY sex reversal 3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 23, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital	Sep 30, 2016	- -

46,XX sex reversal 4 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Mar 23, 2016	Likely pathogenicity based on finding it once in our study inferred de novo in a 31-year-old 46,XX male with hypogonadism, decreased testicular size, and primary testicular failure. This patient has been reported in PMID 27378692. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 23, 2021	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 16, 2021

ClinVar contains an entry for this variant (Variation ID: 265792). This missense change has been observed in individual(s) with NR5A1-related conditions (PMID: 27378692, 27490115, 28033660). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 92 of the NR5A1 protein (p.Arg92Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NR5A1 function (PMID: 27378692). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.2	.;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.91
MutPred		0.49		Loss of disorder (P = 0.0078);Loss of disorder (P = 0.0078);Loss of disorder (P = 0.0078);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		0.041
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886039769; hg19: chr9-127262965;