rs12221497

Positions:

• chr11-47259102-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000467728.5(NR1H3):​c.-115G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,591,672 control chromosomes in the GnomAD database, including 16,759 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1079 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15680 hom.)
• Consequence: NR1H3 ENST00000467728.5 5_prime_UTR
• Scores: Splicing: ADA: 0.00003002
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1H3	NM_005693.4	c.-37-78G>A		intron_variant		ENST00000441012.7	NP_005684.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1H3	ENST00000441012.7	c.-37-78G>A		intron_variant		1	NM_005693.4	ENSP00000387946	P1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16817 AN: 152172 Hom.: 1083 Cov.: 32

Gnomad AFR AF: 0.0575

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0785

Gnomad ASJ AF: 0.0930

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.143 AC: 205133 AN: 1439382 Hom.: 15680 Cov.: 31 AF XY: 0.145 AC XY: 103506 AN XY: 713222

Gnomad4 AFR exome AF: 0.0559

Gnomad4 AMR exome AF: 0.0499

Gnomad4 ASJ exome AF: 0.0888

Gnomad4 EAS exome AF: 0.0876

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.110 AC: 16810 AN: 152290 Hom.: 1079 Cov.: 32 AF XY: 0.111 AC XY: 8259 AN XY: 74458

Gnomad4 AFR AF: 0.0575

Gnomad4 AMR AF: 0.0783

Gnomad4 ASJ AF: 0.0930

Gnomad4 EAS AF: 0.0952

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.104

Alfa AF: 0.132 Hom.: 2037

Bravo AF: 0.0999

Asia WGS AF: 0.195 AC: 676 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.4
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs12221497; hg19: chr11-47280653;