11-47260552-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005693.4(NR1H3):c.376G>A(p.Val126Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NR1H3 NM_005693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40867144).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H3	NM_005693.4	c.376G>A	p.Val126Ile	missense_variant	4/10	ENST00000441012.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H3	ENST00000441012.7	c.376G>A	p.Val126Ile	missense_variant	4/10	1	NM_005693.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251344 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Nov 05, 2021

The c.376G>A (p.V126I) alteration is located in exon 4 (coding exon 3) of the NR1H3 gene. This alteration results from a G to A substitution at nucleotide position 376, causing the valine (V) at amino acid position 126 to be replaced by an isoleucine (I). 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	0.089
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.36	T;.;.;T;T;.;.;.;T;D;T;D;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.;D;D;D;.;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.20	B;.;B;D;.;P;.;.;.;B;.;B;P;.
Vest4		0.16
MutPred		0.56		.;Loss of MoRF binding (P = 0.1225);Loss of MoRF binding (P = 0.1225);Loss of MoRF binding (P = 0.1225);.;.;.;Loss of MoRF binding (P = 0.1225);.;.;.;.;.;.;
MVP		0.77
MPC		0.41
ClinPred		0.42	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.049
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs761873817; hg19: chr11-47282103; COSMIC: COSV101269779; COSMIC: COSV101269779;