9-124500592-C-T

Position:

• chr9-124500592-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004959.5(NR5A1):​c.368G>A​(p.Gly123Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12451705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.368G>A	p.Gly123Glu	missense_variant	4/7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR5A1	ENST00000373588.9	c.368G>A	p.Gly123Glu	missense_variant	4/7	1	NM_004959.5	ENSP00000362690	P1
NR5A1	ENST00000620110.4	c.368G>A	p.Gly123Glu	missense_variant	4/6	5		ENSP00000483309
NR5A1	ENST00000455734.1	c.368G>A	p.Gly123Glu	missense_variant	4/4	3		ENSP00000393245
NR5A1	ENST00000373587.3	c.40-320G>A		intron_variant		3		ENSP00000362689

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 241878 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460022 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726288

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	.;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	2.0	.;M;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	.;N;D
REVEL	Benign	0.23
Sift	Benign	0.29	.;T;T
Sift4G	Benign	0.28	T;T;.
Polyphen		0.35	.;B;.
Vest4		0.45
MutPred		0.30		Gain of solvent accessibility (P = 0.0062);Gain of solvent accessibility (P = 0.0062);Gain of solvent accessibility (P = 0.0062);
MVP		0.68
MPC		1.0
ClinPred		0.10	T
GERP RS		2.5
Varity_R		0.086
gMVP		0.49

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: rs200163795; hg19: chr9-127262871;