19-50377484-T-C

Variant names:

• chr19-50377484-T-C
• rs2695121
• ENST00000597157.1:c.-122T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000597157.1(NR1H2):​c.-122T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 885,204 control chromosomes in the GnomAD database, including 178,741 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 0.70 (38493 hom., cov: 28)
  • Exomes 𝑓: 0.61 (140248 hom.)
• Consequence: NR1H2 ENST00000597157.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301
• Publications: 42 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000597157.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H2	NM_007121.7	MANE Select	c.-19-103T>C		intron	N/A	NP_009052.4
	NR1H2	NM_001256647.3		c.-19-103T>C		intron	N/A	NP_001243576.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H2	ENST00000597157.1	TSL:1	c.-122T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000469778.1
	NR1H2	ENST00000597157.1	TSL:1	c.-122T>C		5_prime_UTR	Exon 1 of 4	ENSP00000469778.1
	NR1H2	ENST00000253727.10	TSL:1 MANE Select	c.-19-103T>C		intron	N/A	ENSP00000253727.4

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105198 AN: 151412 Hom.: 38414 Cov.: 28

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.689

GnomAD4 exome AF: 0.611 AC: 448040 AN: 733674 Hom.: 140248 Cov.: 10 AF XY: 0.613 AC XY: 232632 AN XY: 379370

African (AFR) AF: 0.931 AC: 15856 AN: 17022

American (AMR) AF: 0.655 AC: 15918 AN: 24316

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 11526 AN: 15652

East Asian (EAS) AF: 0.900 AC: 28631 AN: 31800

South Asian (SAS) AF: 0.691 AC: 38079 AN: 55080

European-Finnish (FIN) AF: 0.563 AC: 25714 AN: 45636

Middle Eastern (MID) AF: 0.668 AC: 2731 AN: 4088

European-Non Finnish (NFE) AF: 0.569 AC: 287142 AN: 504876

Other (OTH) AF: 0.638 AC: 22443 AN: 35204

GnomAD4 genome AF: 0.695 AC: 105341 AN: 151530 Hom.: 38493 Cov.: 28 AF XY: 0.696 AC XY: 51486 AN XY: 74016

African (AFR) AF: 0.923 AC: 38097 AN: 41292

American (AMR) AF: 0.670 AC: 10187 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2579 AN: 3472

East Asian (EAS) AF: 0.875 AC: 4496 AN: 5136

South Asian (SAS) AF: 0.701 AC: 3365 AN: 4800

European-Finnish (FIN) AF: 0.557 AC: 5854 AN: 10510

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.568 AC: 38551 AN: 67814

Other (OTH) AF: 0.691 AC: 1455 AN: 2106

Alfa AF: 0.616 Hom.: 18990

Bravo AF: 0.710

Asia WGS AF: 0.789 AC: 2740 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.68
DANN	Benign	0.76
PhyloP100		-0.30
PromoterAI		-0.0034	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2695121; hg19: chr19-50880741;