Variant chr11-47259916-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_005693.4(NR1H3):c.169G>A(p.Gly57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,456,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

NR1H3
NM_005693.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61

Variant links:

Genes affected

NR1H3 (HGNC:7966): (nuclear receptor subfamily 1 group H member 3) The protein encoded by this gene belongs to the NR1 subfamily of the nuclear receptor superfamily. The NR1 family members are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. This protein is highly expressed in visceral organs, including liver, kidney and intestine. It forms a heterodimer with retinoid X receptor (RXR), and regulates expression of target genes containing retinoid response elements. Studies in mice lacking this gene suggest that it may play an important role in the regulation of cholesterol homeostasis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

NR1H3 links:

NR1H3 (HGNC:):

NR1H3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2287226).

BS2

High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1H3	NM_005693.4 linkuse as main transcript	c.169G>A	p.Gly57Arg	missense_variant	3/10	ENST00000441012.7	NP_005684.2	Q13133-1B4DXU5F1D8N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1H3	ENST00000441012.7 linkuse as main transcript	c.169G>A	p.Gly57Arg	missense_variant	3/10	1	NM_005693.4	ENSP00000387946.2		Q13133-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000417

AC:

AN:

239540

Hom.:

AF XY:

0.0000306

AC XY:

AN XY:

130600

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000297

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1456850

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724490

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000227

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.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.169G>A (p.G57R) alteration is located in exon 3 (coding exon 2) of the NR1H3 gene. This alteration results from a G to A substitution at nucleotide position 169, causing the glycine (G) at amino acid position 57 to be replaced by an arginine (R). 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

0.096

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;.;.;T;T;.;.;.;.;.;T;T;T;T;T;.

Eigen

Benign

-0.046

Eigen_PC

Benign

-0.046

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.83

T;T;T;T;T;D;.;T;T;T;T;.;T;T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.23

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.00050

MutationAssessor

Benign

1.1

.;.;.;.;.;.;L;.;.;.;.;L;.;.;L;L

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.8

.;N;N;N;N;N;N;N;D;D;N;N;D;N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0050

.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.041

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.38

B;.;.;D;.;.;D;.;.;.;.;P;.;.;P;D

Vest4

0.27

MutPred

0.29

.;Gain of methylation at G12 (P = 0.0329);Gain of methylation at G12 (P = 0.0329);Gain of methylation at G12 (P = 0.0329);.;Gain of methylation at G12 (P = 0.0329);.;.;.;Gain of methylation at G12 (P = 0.0329);.;.;.;.;.;.;

MVP

0.83

MPC

0.56

ClinPred

0.11

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.048

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over