rs113506523

Positions:

• chr9-124500444-G-A
• chr9-124500444-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004959.5(NR5A1):​c.516C>T​(p.Ala172Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,583,304 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (32 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (25 hom.)
• Consequence: NR5A1 NM_004959.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.04

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-124500444-G-A is Benign according to our data. Variant chr9-124500444-G-A is described in ClinVar as [Benign]. Clinvar id is 138537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1532/152290) while in subpopulation AFR AF= 0.0355 (1474/41578). AF 95% confidence interval is 0.0339. There are 32 homozygotes in gnomad4. There are 729 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.516C>T	p.Ala172Ala	synonymous_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.516C>T	p.Ala172Ala	synonymous_variant	4/7	1	NM_004959.5	ENSP00000362690.4
NR5A1	ENST00000620110.4	c.516C>T	p.Ala172Ala	synonymous_variant	4/6	5		ENSP00000483309.1
NR5A1	ENST00000455734.1	c.516C>T	p.Ala172Ala	synonymous_variant	4/4	3		ENSP00000393245.1
NR5A1	ENST00000373587.3	c.40-172C>T		intron_variant		3		ENSP00000362689.3

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1512 AN: 152172 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00210 AC: 403 AN: 191534 Hom.: 4 AF XY: 0.00165 AC XY: 174 AN XY: 105204

Gnomad AFR exome AF: 0.0339

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000745

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.000797

GnomAD4 exome AF: 0.00102 AC: 1461 AN: 1431014 Hom.: 25 Cov.: 32 AF XY: 0.000851 AC XY: 604 AN XY: 709416

Gnomad4 AFR exome AF: 0.0361

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000841

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000446

Gnomad4 OTH exome AF: 0.00246

GnomAD4 genome AF: 0.0101 AC: 1532 AN: 152290 Hom.: 32 Cov.: 33 AF XY: 0.00979 AC XY: 729 AN XY: 74466

Gnomad4 AFR AF: 0.0355

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.000959 Hom.: 0

Bravo AF: 0.0112

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 27, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.18
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs113506523; hg19: chr9-127262723;