Genetic Variant NR1H2:c.927+124A>G (chr19-50379305-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_007121.7(NR1H2):c.927+124A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,082,804 control chromosomes in the GnomAD database, including 89 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 0.0091 ( 13 hom., cov: 33)

Exomes 𝑓: 0.010 ( 76 hom. )

Consequence

NR1H2
NM_007121.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0180

Publications

1 publications found

Variant links:

Genes affected

NR1H2 (HGNC:7965): (nuclear receptor subfamily 1 group H member 2) The liver X receptors, LXRA (NR1H3; MIM 602423) and LXRB, form a subfamily of the nuclear receptor superfamily and are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. The inducible LXRA is highly expressed in liver, adrenal gland, intestine, adipose tissue, macrophages, lung, and kidney, whereas LXRB is ubiquitously expressed. Ligand-activated LXRs form obligate heterodimers with retinoid X receptors (RXRs; see MIM 180245) and regulate expression of target genes containing LXR response elements (summary by Korf et al., 2009 [PubMed 19436111]).[supplied by OMIM, Jan 2010]

NR1H2 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=-0.81).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0103 (9630/930456) while in subpopulation MID AF = 0.0233 (103/4414). AF 95% confidence interval is 0.0197. There are 76 homozygotes in GnomAdExome4. There are 4718 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAd4 at 1392 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H2	NM_007121.7 link	c.927+124A>G		intron_variant	Intron 7 of 9	ENST00000253727.10	NP_009052.4
NR1H2	NM_001256647.3 link	c.636+124A>G		intron_variant	Intron 6 of 8		NP_001243576.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H2	ENST00000253727.10 link	c.927+124A>G		intron_variant	Intron 7 of 9	1	NM_007121.7	ENSP00000253727.4

Frequencies

GnomAD3 genomes

AF:

0.00916

AC:

1394

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0458

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0158

GnomAD4 exome

AF:

0.0103

AC:

9630

AN:

930456

Hom.:

AF XY:

0.0101

AC XY:

4718

AN XY:

466424

show subpopulations

African (AFR)

AF:

0.00157

AC:

AN:

21692

American (AMR)

AF:

0.00994

AC:

208

AN:

20918

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

763

AN:

16654

East Asian (EAS)

AF:

0.0000291

AC:

AN:

34406

South Asian (SAS)

AF:

0.00240

AC:

138

AN:

57598

European-Finnish (FIN)

AF:

0.0117

AC:

399

AN:

34130

Middle Eastern (MID)

AF:

0.0233

AC:

103

AN:

4414

European-Non Finnish (NFE)

AF:

0.0108

AC:

7537

AN:

698920

Other (OTH)

AF:

0.0107

AC:

447

AN:

41724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

480

961

1441

1922

2402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

226

452

678

904

1130

<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:

0.00914

AC:

1392

AN:

152348

Hom.:

Cov.:

AF XY:

0.00873

AC XY:

650

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

41588

American (AMR)

AF:

0.0117

AC:

179

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

159

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00290

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00772

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

811

AN:

68024

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0102

Hom.:

Bravo

AF:

0.00899

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.89

(source)

DANN

Benign

0.72

PhyloP100

-0.018

Mutation Taster

=100/0

polymorphism

(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