dbSNP rs777612868: NR6A1:p.Asp355His (chr9-124535894-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_033334.4(NR6A1):c.1063G>C(p.Asp355His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D355N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NR6A1
NM_033334.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.36

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR6A1	NM_033334.4 link	c.1063G>C	p.Asp355His	missense_variant	Exon 7 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.1063G>C	p.Asp355His	missense_variant	Exon 7 of 10	1	NM_033334.4	ENSP00000420267.1	Q15406-1
NR6A1	ENST00000373584.7 link	c.1051G>C	p.Asp351His	missense_variant	Exon 7 of 10	1		ENSP00000362686.3	Q15406-2
NR6A1	ENST00000416460.6 link	c.1048G>C	p.Asp350His	missense_variant	Exon 7 of 10	1		ENSP00000413701.2	Q15406-5
NR6A1	ENST00000344523.8 link	c.1060G>C	p.Asp354His	missense_variant	Exon 7 of 10	5		ENSP00000341135.4	Q15406-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251108

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727228

show subpopulations

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.6

L;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.11

N;N;N;N

REVEL

Pathogenic

0.66

Sift

Uncertain

0.021

D;D;D;D

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.93

P;.;D;.

Vest4

0.64

MutPred

0.38

Loss of helix (P = 0.0558);.;.;.;

MVP

0.72

MPC

1.0

ClinPred

0.72

GERP RS

5.2

Varity_R

0.19

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over