11-47260473-C-T

Variant names:

• chr11-47260473-C-T
• rs2279238
• NM_005693.4:c.297C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_005693.4(NR1H3):​c.297C>T​(p.Ser99Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,614,010 control chromosomes in the GnomAD database, including 40,082 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 0.26 (6319 hom., cov: 33)
  • Exomes 𝑓: 0.19 (33763 hom.)
• Consequence: NR1H3 NM_005693.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 71 publications found

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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005693.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H3	NM_005693.4	MANE Select	c.297C>T	p.Ser99Ser	synonymous	Exon 4 of 10	NP_005684.2	F1D8N1
	NR1H3	NM_001251934.2		c.315C>T	p.Ser105Ser	synonymous	Exon 4 of 10	NP_001238863.1	B4DXU5
	NR1H3	NM_001251935.2		c.315C>T	p.Ser105Ser	synonymous	Exon 4 of 10	NP_001238864.1	B4DXU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H3	ENST00000441012.7	TSL:1 MANE Select	c.297C>T	p.Ser99Ser	synonymous	Exon 4 of 10	ENSP00000387946.2	Q13133-1
	NR1H3	ENST00000616973.4	TSL:1	c.315C>T	p.Ser105Ser	synonymous	Exon 4 of 10	ENSP00000477707.1	B4DXU5
	NR1H3	ENST00000467728.5	TSL:1	c.297C>T	p.Ser99Ser	synonymous	Exon 3 of 9	ENSP00000420656.1	Q13133-1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39264 AN: 152034 Hom.: 6317 Cov.: 33

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.256 AC: 64415 AN: 251222 AF XY: 0.243

Gnomad AFR exome AF: 0.382

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.669

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.189 AC: 276775 AN: 1461856 Hom.: 33763 Cov.: 34 AF XY: 0.189 AC XY: 137212 AN XY: 727232

African (AFR) AF: 0.382 AC: 12793 AN: 33476

American (AMR) AF: 0.370 AC: 16557 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3367 AN: 26136

East Asian (EAS) AF: 0.652 AC: 25875 AN: 39698

South Asian (SAS) AF: 0.238 AC: 20491 AN: 86258

European-Finnish (FIN) AF: 0.266 AC: 14219 AN: 53414

Middle Eastern (MID) AF: 0.163 AC: 940 AN: 5768

European-Non Finnish (NFE) AF: 0.153 AC: 170535 AN: 1111992

Other (OTH) AF: 0.199 AC: 11998 AN: 60396

GnomAD4 genome AF: 0.258 AC: 39278 AN: 152154 Hom.: 6319 Cov.: 33 AF XY: 0.268 AC XY: 19918 AN XY: 74386

African (AFR) AF: 0.381 AC: 15792 AN: 41486

American (AMR) AF: 0.272 AC: 4166 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 455 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3350 AN: 5148

South Asian (SAS) AF: 0.240 AC: 1157 AN: 4830

European-Finnish (FIN) AF: 0.296 AC: 3133 AN: 10596

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10659 AN: 68000

Other (OTH) AF: 0.213 AC: 450 AN: 2114

Alfa AF: 0.189 Hom.: 5451

Bravo AF: 0.265

Asia WGS AF: 0.342 AC: 1186 AN: 3478

EpiCase AF: 0.142

EpiControl AF: 0.134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.8
DANN	Benign	0.77
PhyloP100		-1.2
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2279238; hg19: chr11-47282024; COSMIC: COSV68008887; COSMIC: COSV68008887;