Genetic Variant NR6A1:p.Gly478Ser (chr9-124522716-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033334.4(NR6A1):c.1432G>A(p.Gly478Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NR6A1
NM_033334.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

Variant links:

Genes affected

NR6A1 (HGNC:7985): (nuclear receptor subfamily 6 group A member 1) This gene encodes an orphan nuclear receptor which is a member of the nuclear hormone receptor family. Its expression pattern suggests that it may be involved in neurogenesis and germ cell development. The protein can homodimerize and bind DNA, but in vivo targets have not been identified. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jun 2013]

NR6A1 links:

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ACMG classification

Classification made for transcript

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=0.0582138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR6A1	NM_033334.4 link	c.1432G>A	p.Gly478Ser	missense_variant	Exon 10 of 10	ENST00000487099.7	NP_201591.2	Q15406-1F1D8S0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR6A1	ENST00000487099.7 link	c.1432G>A	p.Gly478Ser	missense_variant	Exon 10 of 10	1	NM_033334.4	ENSP00000420267.1	Q15406-1
NR6A1	ENST00000373584.7 link	c.1420G>A	p.Gly474Ser	missense_variant	Exon 10 of 10	1		ENSP00000362686.3	Q15406-2
NR6A1	ENST00000416460.6 link	c.1417G>A	p.Gly473Ser	missense_variant	Exon 10 of 10	1		ENSP00000413701.2	Q15406-5
NR6A1	ENST00000344523.8 link	c.1429G>A	p.Gly477Ser	missense_variant	Exon 10 of 10	5		ENSP00000341135.4	Q15406-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1428150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707322

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1432G>A (p.G478S) alteration is located in exon 10 (coding exon 10) of the NR6A1 gene. This alteration results from a G to A substitution at nucleotide position 1432, causing the glycine (G) at amino acid position 478 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.0069

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.16

T;.;.;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.058

T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-0.69

N;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.050

N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.035

MutPred

0.14

Gain of phosphorylation at G478 (P = 0.0506);.;.;.;

MVP

0.43

MPC

0.28

ClinPred

0.69

GERP RS

3.7

Varity_R

0.054

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over