Genetic Variant NR1H3:c.-840C>A (chr11-47258377-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000467728.5(NR1H3):c.-840C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 191,796 control chromosomes in the GnomAD database, including 1,443 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1078 hom., cov: 30)

Exomes 𝑓: 0.13 ( 365 hom. )

Consequence

NR1H3
ENST00000467728.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0190

Publications

9 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H3	NM_005693.4 link	c.-38+248C>A		intron_variant	Intron 1 of 9	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.-38+248C>A		intron_variant	Intron 1 of 9	1	NM_005693.4	ENSP00000387946.2		Q13133-1

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16792

AN:

151856

Hom.:

1082

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0575

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.0787

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.0965

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.105

GnomAD4 exome

AF:

0.131

AC:

5208

AN:

39822

Hom.:

365

Cov.:

AF XY:

0.132

AC XY:

2566

AN XY:

19448

show subpopulations

African (AFR)

AF:

0.0471

AC:

AN:

722

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0691

AC:

AN:

246

East Asian (EAS)

AF:

0.114

AC:

AN:

166

South Asian (SAS)

AF:

0.215

AC:

177

AN:

824

European-Finnish (FIN)

AF:

0.146

AC:

AN:

Middle Eastern (MID)

AF:

0.103

AC:

AN:

European-Non Finnish (NFE)

AF:

0.131

AC:

4784

AN:

36406

Other (OTH)

AF:

0.126

AC:

162

AN:

1286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

215

430

646

861

1076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

238

476

714

952

1190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.110

AC:

16785

AN:

151974

Hom.:

1078

Cov.:

AF XY:

0.111

AC XY:

8245

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.0575

AC:

2380

AN:

41410

American (AMR)

AF:

0.0785

AC:

1198

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0931

AC:

323

AN:

3468

East Asian (EAS)

AF:

0.0958

AC:

495

AN:

5168

South Asian (SAS)

AF:

0.229

AC:

1100

AN:

4806

European-Finnish (FIN)

AF:

0.131

AC:

1385

AN:

10558

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.141

AC:

9609

AN:

67982

Other (OTH)

AF:

0.104

AC:

220

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

753

1506

2259

3012

3765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0606

Hom.:

Bravo

AF:

0.0999

Asia WGS

AF:

0.195

AC:

676

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.1

(source)

DANN

Benign

0.46

PhyloP100

0.019

PromoterAI

-0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over