9-124482917-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004959.5(NR5A1):c.1227C>G(p.Tyr409Ter) variant causes a stop gained change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR5A1 NM_004959.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.21

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-124482917-G-C is Pathogenic according to our data. Variant chr9-124482917-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 583141.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR5A1	NM_004959.5	c.1227C>G	p.Tyr409Ter	stop_gained	7/7	ENST00000373588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR5A1	ENST00000373588.9	c.1227C>G	p.Tyr409Ter	stop_gained	7/7	1	NM_004959.5	P1
NR5A1	ENST00000620110.4	c.1107C>G	p.Tyr369Ter	stop_gained	6/6	5
NR5A1	ENST00000373587.3	c.579C>G	p.Tyr193Ter	stop_gained	5/5	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 23, 2018

This sequence change results in a premature translational stop signal in the NR5A1 gene (p.Tyr409*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 53 amino acids of the NR5A1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with 46,XY disorder of sex reversal and a family history of hypospadias and asplenia (PMID: 28032338). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. The observation of one or more variants downstream of this variant (p.Leu423Trpfs*7, p.Cys412*, p.Glu445*, p.Leu419Gln, p.Gln460Leu, and p.Leu437Gln) in affected individuals suggests that this may be a clinically significant region of the NR5A1 protein (PMID: 28326187, 27899157, 28938747, 17200175, 28033660, 26139438). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	41
Dann	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D
Vest4		0.68
GERP RS		5.1

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: rs1564146922; hg19: chr9-127245196;