19-50377484-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000597157.1(NR1H2):​c.-122T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

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>G		intron	N/A	NP_009052.4
	NR1H2	NM_001256647.3		c.-19-103T>G		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>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000469778.1
	NR1H2	ENST00000597157.1	TSL:1	c.-122T>G		5_prime_UTR	Exon 1 of 4	ENSP00000469778.1
	NR1H2	ENST00000253727.10	TSL:1 MANE Select	c.-19-103T>G		intron	N/A	ENSP00000253727.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000136 AC: 1 AN: 735430 Hom.: 0 Cov.: 10 AF XY: 0.00000263 AC XY: 1 AN XY: 380224

African (AFR) AF: 0.00 AC: 0 AN: 17024

American (AMR) AF: 0.00 AC: 0 AN: 24372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15672

East Asian (EAS) AF: 0.00 AC: 0 AN: 31826

South Asian (SAS) AF: 0.0000181 AC: 1 AN: 55178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4098

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 506272

Other (OTH) AF: 0.00 AC: 0 AN: 35266

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.61
DANN	Benign	0.73
PhyloP100		-0.30
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3

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;