chr9-124536128-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033334.4(NR6A1):​c.829G>T​(p.Ala277Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. A277T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NR6A1 NM_033334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064965546).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR6A1	NM_033334.4	MANE Select	c.829G>T	p.Ala277Ser	missense	Exon 7 of 10	NP_201591.2
	NR6A1	NM_001410996.1		c.826G>T	p.Ala276Ser	missense	Exon 7 of 10	NP_001397925.1	Q15406-4
	NR6A1	NM_001278546.2		c.817G>T	p.Ala273Ser	missense	Exon 7 of 10	NP_001265475.1	F1DAM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR6A1	ENST00000487099.7	TSL:1 MANE Select	c.829G>T	p.Ala277Ser	missense	Exon 7 of 10	ENSP00000420267.1	Q15406-1
	NR6A1	ENST00000373584.7	TSL:1	c.817G>T	p.Ala273Ser	missense	Exon 7 of 10	ENSP00000362686.3	Q15406-2
	NR6A1	ENST00000416460.6	TSL:1	c.814G>T	p.Ala272Ser	missense	Exon 7 of 10	ENSP00000413701.2	Q15406-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459624 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725736

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5486

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110560

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.69	N
PhyloP100		2.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.80	N
REVEL	Benign	0.20
Sift	Benign	0.78	T
Sift4G	Benign	0.74	T
Polyphen		0.0040	B
Vest4		0.19
MutPred		0.36		Loss of catalytic residue at A277 (P = 0.0366)
MVP		0.27
MPC		0.26
ClinPred		0.26	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.29
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs764847595; hg19: chr9-127298407;