11-47259814-C-T

Variant names:

• chr11-47259814-C-T
• rs139438525
• NM_005693.4:c.67C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005693.4(NR1H3):​c.67C>T​(p.Pro23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P23T) has been classified as Uncertain significance.

• 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: -0.645
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05881518).

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.67C>T	p.Pro23Ser	missense	Exon 3 of 10	NP_005684.2	F1D8N1
	NR1H3	NM_001251934.2		c.85C>T	p.Pro29Ser	missense	Exon 3 of 10	NP_001238863.1	B4DXU5
	NR1H3	NM_001251935.2		c.85C>T	p.Pro29Ser	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.67C>T	p.Pro23Ser	missense	Exon 3 of 10	ENSP00000387946.2	Q13133-1
	NR1H3	ENST00000616973.4	TSL:1	c.85C>T	p.Pro29Ser	missense	Exon 3 of 10	ENSP00000477707.1	B4DXU5
	NR1H3	ENST00000467728.5	TSL:1	c.67C>T	p.Pro23Ser	missense	Exon 2 of 9	ENSP00000420656.1	Q13133-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459886 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726236

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111902

Other (OTH) AF: 0.0000166 AC: 1 AN: 60212

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.92
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.65
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.021
Sift	Benign	0.15	T
Sift4G	Uncertain	0.041	D
Polyphen		0.0	B
Vest4		0.10
MutPred		0.29		Loss of loop (P = 0.0073)
MVP		0.26
MPC		0.45
ClinPred		0.040	T
GERP RS		0.033
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.077
Mutation Taster		=96/4	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: rs139438525; hg19: chr11-47281365;