chr9-124500326-C-A

Variant names:

• chr9-124500326-C-A
• NM_004959.5:c.634G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_004959.5(NR5A1):​c.634G>T​(p.Gly212Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. G212S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-124500326-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.31619376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.634G>T	p.Gly212Cys	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.634G>T	p.Gly212Cys	missense_variant	Exon 4 of 7	1	NM_004959.5	ENSP00000362690.4
NR5A1	ENST00000620110.4	c.634G>T	p.Gly212Cys	missense_variant	Exon 4 of 6	5		ENSP00000483309.1
NR5A1	ENST00000373587.3	c.40-54G>T		intron_variant	Intron 1 of 4	3		ENSP00000362689.3
NR5A1	ENST00000455734.1	c.*101G>T		downstream_gene_variant		3		ENSP00000393245.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405766 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 694180

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: 0.00

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	0.094
BayesDel_addAF	Benign	0.0047	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.048	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	.;N
REVEL	Benign	0.16
Sift	Benign	0.046	.;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.32	.;B
Vest4		0.43
MutPred		0.31		Gain of catalytic residue at G212 (P = 0.0435);Gain of catalytic residue at G212 (P = 0.0435);
MVP		0.56
MPC		1.4
ClinPred		0.35	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-127262605;