11-47259902-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005693.4(NR1H3):c.155G>T(p.Gly52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,611,938 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0065 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 8 hom. )

Consequence

NR1H3
NM_005693.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.610

Variant links:

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]

NR1H3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032809675).

BP6

Variant 11-47259902-G-T is Benign according to our data. Variant chr11-47259902-G-T is described in ClinVar as [Benign]. Clinvar id is 779196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00652 (993/152278) while in subpopulation AFR AF= 0.0228 (948/41558). AF 95% confidence interval is 0.0216. There are 14 homozygotes in gnomad4. There are 475 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 993 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H3	NM_005693.4 link	c.155G>T	p.Gly52Val	missense_variant	Exon 3 of 10	ENST00000441012.7	NP_005684.2	Q13133-1B4DXU5F1D8N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H3	ENST00000441012.7 link	c.155G>T	p.Gly52Val	missense_variant	Exon 3 of 10	1	NM_005693.4	ENSP00000387946.2		Q13133-1

Frequencies

GnomAD3 genomes

AF:

0.00652

AC:

992

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00174

AC:

424

AN:

244366

Hom.:

AF XY:

0.00107

AC XY:

142

AN XY:

133062

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.000995

Gnomad ASJ exome

AF:

0.000818

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000365

Gnomad OTH exome

AF:

0.000672

GnomAD4 exome

AF:

0.000776

AC:

1133

AN:

1459660

Hom.:

Cov.:

AF XY:

0.000629

AC XY:

457

AN XY:

726072

show subpopulations

Gnomad4 AFR exome

AF:

0.0266

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.000885

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00183

GnomAD4 genome

AF:

0.00652

AC:

993

AN:

152278

Hom.:

Cov.:

AF XY:

0.00638

AC XY:

475

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0228

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.000896

Hom.:

Bravo

AF:

0.00755

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00203

AC:

246

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Benign

1.2

DANN

Benign

0.66

DEOGEN2

Benign

0.097

T;.;.;T;T;.;.;.;.;.;T;T;T;T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.79

T;T;T;T;T;T;.;T;T;T;T;.;T;T;T;T

MetaRNN

Benign

0.0033

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.0

.;.;.;.;.;.;L;.;.;.;.;L;.;.;L;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.4

.;N;N;N;N;N;N;N;D;N;N;N;D;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.079

.;T;T;D;T;D;T;T;T;D;T;T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;B;.;.;B;.;.;.;.;B;.;.;B;B

Vest4

0.15

MVP

0.64

MPC

0.56

ClinPred

0.0028

GERP RS

-0.83

Varity_R

0.041

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over