chr9-124500523-C-G

Variant names:

• chr9-124500523-C-G
• rs1110061
• NM_004959.5:c.437G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004959.5(NR5A1):​c.437G>C​(p.Gly146Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 1,607,478 control chromosomes in the GnomAD database, including 25,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (12009 hom., cov: 33)
  • Exomes 𝑓: 0.046 (13192 hom.)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0130
• Publications: 54 publications found

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 Gene-Disease associations (from GenCC):

• 46,XX sex reversal 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46,XY sex reversal 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• premature ovarian failure 7

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XX ovotesticular disorder of sex development

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XX sex reversal 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.3359 (below the threshold of 3.09). Trascript score misZ: 2.4094 (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XY sex reversal 3, 46,XX sex reversal 4, 46,XX ovotesticular disorder of sex development, premature ovarian failure 7, spermatogenic failure 8, 46,XY partial gonadal dysgenesis, 46 XX gonadal dysgenesis, male infertility with azoospermia or oligozoospermia due to single gene mutation, 46,XX sex reversal 1, 46,XY complete gonadal dysgenesis.
• BP4: Computational evidence support a benign effect (MetaRNN=8.3544745E-7).
• BP6: Variant 9-124500523-C-G is Benign according to our data. Variant chr9-124500523-C-G is described in ClinVar as Benign. ClinVar VariationId is 259591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004959.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR5A1	NM_004959.5	MANE Select	c.437G>C	p.Gly146Ala	missense	Exon 4 of 7	NP_004950.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR5A1	ENST00000373588.9	TSL:1 MANE Select	c.437G>C	p.Gly146Ala	missense	Exon 4 of 7	ENSP00000362690.4
	NR5A1	ENST00000950385.1		c.437G>C	p.Gly146Ala	missense	Exon 4 of 7	ENSP00000620444.1
	NR5A1	ENST00000911688.1		c.437G>C	p.Gly146Ala	missense	Exon 4 of 7	ENSP00000581746.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35784 AN: 152062 Hom.: 11965 Cov.: 33

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.101 AC: 23547 AN: 233592 AF XY: 0.0877

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.0626

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.348

Gnomad FIN exome AF: 0.00578

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0623

GnomAD4 exome AF: 0.0458 AC: 66704 AN: 1455298 Hom.: 13192 Cov.: 32 AF XY: 0.0442 AC XY: 32004 AN XY: 724016

African (AFR) AF: 0.771 AC: 25769 AN: 33436

American (AMR) AF: 0.0679 AC: 3028 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 609 AN: 26052

East Asian (EAS) AF: 0.303 AC: 12015 AN: 39620

South Asian (SAS) AF: 0.0858 AC: 7384 AN: 86100

European-Finnish (FIN) AF: 0.00712 AC: 346 AN: 48580

Middle Eastern (MID) AF: 0.0788 AC: 448 AN: 5688

European-Non Finnish (NFE) AF: 0.0108 AC: 12039 AN: 1111044

Other (OTH) AF: 0.0841 AC: 5066 AN: 60204

GnomAD4 genome AF: 0.236 AC: 35886 AN: 152180 Hom.: 12009 Cov.: 33 AF XY: 0.232 AC XY: 17273 AN XY: 74416

African (AFR) AF: 0.740 AC: 30695 AN: 41492

American (AMR) AF: 0.107 AC: 1633 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3470

East Asian (EAS) AF: 0.325 AC: 1677 AN: 5156

South Asian (SAS) AF: 0.108 AC: 520 AN: 4824

European-Finnish (FIN) AF: 0.00423 AC: 45 AN: 10626

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 837 AN: 67990

Other (OTH) AF: 0.181 AC: 383 AN: 2114

Alfa AF: 0.0761 Hom.: 964

Bravo AF: 0.266

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.695 AC: 3016

ESP6500EA AF: 0.0153 AC: 130

ExAC AF: 0.109 AC: 13098

Asia WGS AF: 0.234 AC: 811 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0160

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	46,XY disorder of sex development (1)
-	-	1	Oligosynaptic infertility;C2751824:46,XY disorder of sex development (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	8.4
DANN	Benign	0.068
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.013
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.5	N
REVEL	Uncertain	0.31
Sift	Benign	0.86	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.072
MPC		0.80
ClinPred		0.000019	T
GERP RS		-0.61
PromoterAI		-0.023	Neutral
Varity_R		0.038
gMVP		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1110061; hg19: chr9-127262802; COSMIC: COSV65295243;