9-124482921-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_004959.5(NR5A1):c.1223A>C(p.His408Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.33

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain NR LBD (size 237) in uniprot entity STF1_HUMAN there are 48 pathogenic changes around while only 0 benign (100%) in NM_004959.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-124482921-T-G is Pathogenic according to our data. Variant chr9-124482921-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1202604.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR5A1	NM_004959.5	c.1223A>C	p.His408Pro	missense_variant	7/7	ENST00000373588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR5A1	ENST00000373588.9	c.1223A>C	p.His408Pro	missense_variant	7/7	1	NM_004959.5	P1
NR5A1	ENST00000620110.4	c.1103A>C	p.His368Pro	missense_variant	6/6	5
NR5A1	ENST00000373587.3	c.575A>C	p.His192Pro	missense_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Disorder of sexual differentiation Pathogenic:1

Pathogenic, no assertion criteria provided

research

Human Developmental Genetics, Institut Pasteur

Aug 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.96	.;P;.
Vest4		0.50
MutPred		0.50		.;Loss of helix (P = 0.1299);.;
MVP		0.84
MPC		1.2
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.70

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: chr9-127245200;