11-47261318-C-T

Position:

• chr11-47261318-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005693.4(NR1H3):​c.577C>T​(p.Pro193Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NR1H3 NM_005693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10266286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H3	NM_005693.4	c.577C>T	p.Pro193Ser	missense_variant	5/10	ENST00000441012.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H3	ENST00000441012.7	c.577C>T	p.Pro193Ser	missense_variant	5/10	1	NM_005693.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727232

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2023

The c.577C>T (p.P193S) alteration is located in exon 5 (coding exon 4) of the NR1H3 gene. This alteration results from a C to T substitution at nucleotide position 577, causing the proline (P) at amino acid position 193 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.8
DANN	Benign	0.87
DEOGEN2	Benign	0.060	T;.;.;T;T;.;.;.;T;T;T;T;.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;.;T;T;.;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.069	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.90	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.41	T;T;T;T;T;T;T;D;T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;.;.;B;.;.;B;.;B;B;.
Vest4		0.15
MutPred		0.33		.;Loss of catalytic residue at P148 (P = 0.0047);Loss of catalytic residue at P148 (P = 0.0047);Loss of catalytic residue at P148 (P = 0.0047);.;.;.;.;.;.;.;.;.;.;
MVP		0.47
MPC		0.45
ClinPred		0.034	T
GERP RS		0.67
Varity_R		0.026
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47282869;