11-47260427-G-C

Variant names:

• chr11-47260427-G-C
• rs760894618
• NM_005693.4:c.251G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005693.4(NR1H3):​c.251G>C​(p.Arg84Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,988 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NR1H3 NM_005693.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.72

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]

ACMG classification

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, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H3	NM_005693.4	c.251G>C	p.Arg84Pro	missense_variant	Exon 4 of 10	ENST00000441012.7	NP_005684.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H3	ENST00000441012.7	c.251G>C	p.Arg84Pro	missense_variant	Exon 4 of 10	1	NM_005693.4	ENSP00000387946.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249438 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134934

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: 6.84e-7 AC: 1 AN: 1460988 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726690

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.;T;T;.;.;.;T;D;T;D;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.;D;D;D;.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.1	.;.;.;.;.;L;.;.;.;L;.;L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	.;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0030	.;D;D;D;D;D;D;T;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;T;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D;.;.;.;D;.;D;D
Vest4		0.57
MutPred		0.36		.;Gain of glycosylation at R39 (P = 0.0155);Gain of glycosylation at R39 (P = 0.0155);Gain of glycosylation at R39 (P = 0.0155);.;.;.;Gain of glycosylation at R39 (P = 0.0155);.;.;.;.;.;
MVP		0.90
MPC		1.6
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.61

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

Other links and lift over

dbSNP: rs760894618; hg19: chr11-47281978;