11-47259913-G-A

Variant names:

• chr11-47259913-G-A
• rs1365123122
• NM_005693.4:c.166G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005693.4(NR1H3):​c.166G>A​(p.Val56Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NR1H3 NM_005693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.321
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.081499904).

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.166G>A	p.Val56Met	missense	Exon 3 of 10	NP_005684.2	F1D8N1
	NR1H3	NM_001251934.2		c.184G>A	p.Val62Met	missense	Exon 3 of 10	NP_001238863.1	B4DXU5
	NR1H3	NM_001251935.2		c.184G>A	p.Val62Met	missense	Exon 3 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.166G>A	p.Val56Met	missense	Exon 3 of 10	ENSP00000387946.2	Q13133-1
	NR1H3	ENST00000616973.4	TSL:1	c.184G>A	p.Val62Met	missense	Exon 3 of 10	ENSP00000477707.1	B4DXU5
	NR1H3	ENST00000467728.5	TSL:1	c.166G>A	p.Val56Met	missense	Exon 2 of 9	ENSP00000420656.1	Q13133-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458100 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725224

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53086

Middle Eastern (MID) AF: 0.000366 AC: 2 AN: 5464

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110384

Other (OTH) AF: 0.0000332 AC: 2 AN: 60160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00793067), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	0.34
DANN	Benign	0.78
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.32
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.059
Sift	Benign	0.19	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.096
MutPred		0.21		Gain of phosphorylation at T8 (P = 0.1975)
MVP		0.71
MPC		0.45
ClinPred		0.031	T
GERP RS		-2.6
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.14
Mutation Taster		=99/1	polymorphism

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: rs1365123122; hg19: chr11-47281464;