9-124536128-C-T

Variant names:

• chr9-124536128-C-T
• rs764847595
• NM_033334.4:c.829G>A

Variant summary

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

The NM_033334.4(NR6A1):​c.829G>A​(p.Ala277Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,611,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NR6A1 NM_033334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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]

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=0.043862283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR6A1	NM_033334.4	c.829G>A	p.Ala277Thr	missense_variant	Exon 7 of 10	ENST00000487099.7	NP_201591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR6A1	ENST00000487099.7	c.829G>A	p.Ala277Thr	missense_variant	Exon 7 of 10	1	NM_033334.4	ENSP00000420267.1
NR6A1	ENST00000373584.7	c.817G>A	p.Ala273Thr	missense_variant	Exon 7 of 10	1		ENSP00000362686.3
NR6A1	ENST00000416460.6	c.814G>A	p.Ala272Thr	missense_variant	Exon 7 of 10	1		ENSP00000413701.2
NR6A1	ENST00000344523.8	c.826G>A	p.Ala276Thr	missense_variant	Exon 7 of 10	5		ENSP00000341135.4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000282 AC: 7 AN: 248536 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134570

Gnomad AFR exome AF: 0.000187

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: 0.0000269

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1459626 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 725738

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74428

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000389 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.829G>A (p.A277T) alteration is located in exon 7 (coding exon 7) of the NR6A1 gene. This alteration results from a G to A substitution at nucleotide position 829, causing the alanine (A) at amino acid position 277 to be replaced by a threonine (T). 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	0.064
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.69	N;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.56	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.58	T;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.18
MutPred		0.38		Loss of helix (P = 0.1299);.;.;.;
MVP		0.19
MPC		0.27
ClinPred		0.046	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs764847595; hg19: chr9-127298407;