9-124482834-A-G

Position:

• chr9-124482834-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_004959.5(NR5A1):​c.1310T>C​(p.Leu437Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L437Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.26

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-124482834-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.1310T>C	p.Leu437Pro	missense_variant	7/7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR5A1	ENST00000373588.9	c.1310T>C	p.Leu437Pro	missense_variant	7/7	1	NM_004959.5	ENSP00000362690	P1
NR5A1	ENST00000620110.4	c.1190T>C	p.Leu397Pro	missense_variant	6/6	5		ENSP00000483309
NR5A1	ENST00000373587.3	c.662T>C	p.Leu221Pro	missense_variant	5/5	3		ENSP00000362689

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

NR5A1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2024

The NR5A1 c.1310T>C variant is predicted to result in the amino acid substitution p.Leu437Pro. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. However, another missense variant, c.1310T>A (p.Leu437Gln), at the same residue has been found in the heterozygous state in two individuals with disorders of sex development (DSD) (Lin et al. 2007. PubMed ID: 17200175; Sreenivasan et al. 2018. PubMed ID: 30067310). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.4	.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.95
MutPred		0.93		.;Gain of disorder (P = 0.0134);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-127245113;