chr9-124500523-C-T

Variant names:

• chr9-124500523-C-T
• NM_004959.5:c.437G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004959.5(NR5A1):​c.437G>A​(p.Gly146Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G146A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0130

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028630912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.437G>A	p.Gly146Glu	missense_variant	Exon 4 of 7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR5A1	ENST00000373588.9	c.437G>A	p.Gly146Glu	missense_variant	Exon 4 of 7	1	NM_004959.5	ENSP00000362690.4
NR5A1	ENST00000620110.4	c.437G>A	p.Gly146Glu	missense_variant	Exon 4 of 6	5		ENSP00000483309.1
NR5A1	ENST00000455734.1	c.437G>A	p.Gly146Glu	missense_variant	Exon 4 of 4	3		ENSP00000393245.1
NR5A1	ENST00000373587.3	c.40-251G>A		intron_variant	Intron 1 of 4	3		ENSP00000362689.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455312 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724024

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.30	.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.44	T;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.0	.;N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.19	.;N;N
REVEL	Benign	0.26
Sift	Benign	0.75	.;T;T
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0090	.;B;.
Vest4		0.17
MutPred		0.22		Gain of glycosylation at P147 (P = 0.0866);Gain of glycosylation at P147 (P = 0.0866);Gain of glycosylation at P147 (P = 0.0866);
MVP		0.55
MPC		0.98
ClinPred		0.042	T
GERP RS		-0.61
Varity_R		0.034
gMVP		0.28

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: chr9-127262802;