9-124482934-A-C

Position:

• chr9-124482934-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004959.5(NR5A1):​c.1210T>G​(p.Tyr404Asp) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P: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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 9-124482934-A-C is Pathogenic according to our data. Variant chr9-124482934-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 216976.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.1210T>G	p.Tyr404Asp	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.1210T>G	p.Tyr404Asp	missense_variant	7/7	1	NM_004959.5	ENSP00000362690	P1
NR5A1	ENST00000620110.4	c.1090T>G	p.Tyr364Asp	missense_variant	6/6	5		ENSP00000483309
NR5A1	ENST00000373587.3	c.562T>G	p.Tyr188Asp	missense_variant	5/5	3		ENSP00000362689

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

May 27, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.3	.;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.87
MutPred		0.84		.;Gain of disorder (P = 0.0975);.;
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.85

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: rs863224904; hg19: chr9-127245213;