11-47261296-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005693.4(NR1H3):c.555A>T(p.Glu185Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000075 (0 hom.)
• Consequence: NR1H3 NM_005693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.307

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07713735).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H3	NM_005693.4	c.555A>T	p.Glu185Asp	missense_variant	5/10	ENST00000441012.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H3	ENST00000441012.7	c.555A>T	p.Glu185Asp	missense_variant	5/10	1	NM_005693.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251420 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135906

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: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000330 AC: 4

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

Jan 04, 2024

The c.555A>T (p.E185D) alteration is located in exon 5 (coding exon 4) of the NR1H3 gene. This alteration results from a A to T substitution at nucleotide position 555, causing the glutamic acid (E) at amino acid position 185 to be replaced by an aspartic acid (D). 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	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	10
Dann	Uncertain	0.99
DEOGEN2	Benign	0.058	T;.;.;T;T;.;.;.;T;T;T;T;.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;.;T;T;.;T;T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.077	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N
PrimateAI	Benign	0.48	T
Sift4G	Benign	0.52	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;B;.;.;B;.;.;B;.;B;B;.
Vest4		0.21
MutPred		0.24		.;Gain of MoRF binding (P = 0.1294);Gain of MoRF binding (P = 0.1294);Gain of MoRF binding (P = 0.1294);.;.;.;.;.;.;.;.;.;.;
MVP		0.72
MPC		0.41
ClinPred		0.039	T
GERP RS		-1.6
Varity_R		0.059
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs763782725; hg19: chr11-47282847;