11-47259253-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005693.4(NR1H3):c.37C>T(p.Pro13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: NR1H3 NM_005693.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.198

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046691746).
• BP6: Variant 11-47259253-C-T is Benign according to our data. Variant chr11-47259253-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3201881.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H3	NM_005693.4	c.37C>T	p.Pro13Ser	missense_variant	2/10	ENST00000441012.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H3	ENST00000441012.7	c.37C>T	p.Pro13Ser	missense_variant	2/10	1	NM_005693.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000437 AC: 11 AN: 251496 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135922

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.000103 AC XY: 75 AN XY: 727248

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: 0.000126

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.5
Dann	Benign	0.75
DEOGEN2	Benign	0.059	T;.;.;.;T;T;T;T;T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.60	T;.;T;T;T;.;T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.047	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.24	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;B;.;.;B;B
Vest4		0.069, 0.043, 0.044
MutPred		0.34		Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);Loss of catalytic residue at P13 (P = 4e-04);
MVP		0.30
MPC		0.45
ClinPred		0.024	T
GERP RS		0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026

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: rs769526206; hg19: chr11-47280804;