chr11-47259833-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_005693.4(NR1H3):c.86G>A(p.Ser29Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,612,336 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 1 hom. )
Consequence
NR1H3
NM_005693.4 missense
NM_005693.4 missense
Scores
15
Clinical Significance
Conservation
PhyloP100: 0.802
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.046500355).
BS2
?
High AC in GnomAd at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NR1H3 | NM_005693.4 | c.86G>A | p.Ser29Asn | missense_variant | 3/10 | ENST00000441012.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NR1H3 | ENST00000441012.7 | c.86G>A | p.Ser29Asn | missense_variant | 3/10 | 1 | NM_005693.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152222Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250436Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135604
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1460114Hom.: 1 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 726350
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GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
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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 | Aug 12, 2021 | The c.86G>A (p.S29N) 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 86, causing the serine (S) at amino acid position 29 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T;.;.;.;T;T;T;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;.;T;T;T;.;T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N;N;N;N
PrimateAI
Benign
T
Sift4G
Benign
T;T;T;T;T;T;T;T;T;T;T
Polyphen
B;.;B;.;.;.;B;.;.;B;B
Vest4
MutPred
0.33
.;Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP
MPC
0.42
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at