rs10838681

Positions:

• chr11-47253513-G-A
• chr11-47253513-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000616973.4(NR1H3):​c.61+4649G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 152,000 control chromosomes in the GnomAD database, including 10,020 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 0.34 (10020 hom., cov: 32)
• Consequence: NR1H3 ENST00000616973.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.201

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1H3	NM_001130102.3	c.-93+4514G>A		intron_variant			NP_001123574.1
NR1H3	NM_001251934.2	c.61+4649G>A		intron_variant			NP_001238863.1
NR1H3	NM_001251935.2	c.61+4649G>A		intron_variant			NP_001238864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1H3	ENST00000395397.7	c.-93+4514G>A		intron_variant		1		ENSP00000378793
NR1H3	ENST00000616973.4	c.61+4649G>A		intron_variant		1		ENSP00000477707
NR1H3	ENST00000527464.5	n.282+4649G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52266 AN: 151880 Hom.: 10013 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.295

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.344 AC: 52293 AN: 152000 Hom.: 10020 Cov.: 32 AF XY: 0.353 AC XY: 26198 AN XY: 74308

Gnomad4 AFR AF: 0.450

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.705

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.291

Alfa AF: 0.265 Hom.: 10468

Bravo AF: 0.347

Asia WGS AF: 0.426 AC: 1479 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.48
DANN	Benign	0.46

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10838681; hg19: chr11-47275064;