rs121918656

Positions:

• chr9-124503393-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The ENST00000373588.9(NR5A1):​c.3G>A​(p.Met1?) variant causes a start lost 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR5A1 ENST00000373588.9 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.89

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000373588.9 (NR5A1) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-124503393-C-T is Pathogenic according to our data. Variant chr9-124503393-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12806.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-124503393-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.3G>A	p.Met1?	start_lost	2/7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR5A1	ENST00000373588.9	c.3G>A	p.Met1?	start_lost	2/7	1	NM_004959.5	ENSP00000362690	P1
NR5A1	ENST00000620110.4	c.3G>A	p.Met1?	start_lost	2/6	5		ENSP00000483309
NR5A1	ENST00000455734.1	c.3G>A	p.Met1?	start_lost	2/4	3		ENSP00000393245

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Premature ovarian failure 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 19, 2009

- -

46,XY sex reversal 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 19, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.82	D
MutationTaster	Benign	1.0	A
PROVEAN	Benign	-1.6	.;N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.011	.;D;D
Sift4G	Uncertain	0.020	D;D;.
Polyphen		0.94	.;P;.
Vest4		0.94
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0542);Gain of catalytic residue at M1 (P = 0.0542);Gain of catalytic residue at M1 (P = 0.0542);
MVP		0.99
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.72

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: rs121918656; hg19: chr9-127265672; COSMIC: COSV105301055; COSMIC: COSV105301055;