11-47248704-C-T

Position:

• chr11-47248704-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001251934.2(NR1H3):​c.-100C>T 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 0.341 in 1,610,240 control chromosomes in the GnomAD database, including 102,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13968 hom., cov: 32)
  • Exomes 𝑓: 0.33 (88813 hom.)
• Consequence: NR1H3 NM_001251934.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.35

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]

ACP2 (HGNC:123): (acid phosphatase 2, lysosomal) The protein encoded by this gene belongs to the histidine acid phosphatase family, which hydrolyze orthophosphoric monoesters to alcohol and phosphate. This protein is localized to the lysosomal membrane, and is chemically and genetically distinct from the red cell acid phosphatase. Mice lacking this gene showed multiple defects, including bone structure alterations, lysosomal storage defects, and an increased tendency towards seizures. An enzymatically-inactive allele of this gene in mice showed severe growth retardation, hair-follicle abnormalities, and an ataxia-like phenotype. Alternatively spliced transcript variants have been found for this gene. A C-terminally extended isoform is also predicted to be produced by the use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism. [provided by RefSeq, Oct 2017]

NR1H3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5510478E-6).
• BP6: Variant 11-47248704-C-T is Benign according to our data. Variant chr11-47248704-C-T is described in ClinVar as [Benign]. Clinvar id is 558909.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACP2	NM_001610.4	c.86G>A	p.Arg29Gln	missense_variant	1/11	ENST00000672073.1	NP_001601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACP2	ENST00000672073.1	c.86G>A	p.Arg29Gln	missense_variant	1/11		NM_001610.4	ENSP00000500291.1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61611 AN: 152012 Hom.: 13953 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.343

GnomAD3 exomes AF: 0.392 AC: 95049 AN: 242358 Hom.: 21059 AF XY: 0.383 AC XY: 50337 AN XY: 131300

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.757

Gnomad SAS exome AF: 0.456

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.335 AC: 488164 AN: 1458110 Hom.: 88813 Cov.: 46 AF XY: 0.336 AC XY: 243674 AN XY: 724988

Gnomad4 AFR exome AF: 0.573

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.742

Gnomad4 SAS exome AF: 0.458

Gnomad4 FIN exome AF: 0.408

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.344

GnomAD4 genome AF: 0.405 AC: 61660 AN: 152130 Hom.: 13968 Cov.: 32 AF XY: 0.415 AC XY: 30845 AN XY: 74384

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.360

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.463

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.339

Alfa AF: 0.313 Hom.: 16309

Bravo AF: 0.407

TwinsUK AF: 0.290 AC: 1074

ALSPAC AF: 0.306 AC: 1179

ESP6500AA AF: 0.559 AC: 2452

ESP6500EA AF: 0.288 AC: 2478

ExAC AF: 0.386 AC: 46834

Asia WGS AF: 0.547 AC: 1899 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T;.;T;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.047	T;T;T;.;T
MetaRNN	Benign	0.0000026	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N;.;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.78	N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.82	T;T;T;.;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.040
MPC		0.41
ClinPred		0.034	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.041
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs2167079; hg19: chr11-47270255; COSMIC: COSV57042169; COSMIC: COSV57042169;