chr11-47248704-C-T

Variant names:

• chr11-47248704-C-T
• rs2167079
• ENST00000616973.4:c.-100C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000616973.4(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 ENST00000616973.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.35
• Publications: 69 publications found

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]

ACP2 Gene-Disease associations (from GenCC):

• lysosomal acid phosphatase deficiency

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000616973.4. 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
	ACP2	NM_001610.4	MANE Select	c.86G>A	p.Arg29Gln	missense	Exon 1 of 11	NP_001601.1
	NR1H3	NM_001251934.2		c.-100C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	NP_001238863.1
	NR1H3	NM_001251935.2		c.-100C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	NP_001238864.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H3	ENST00000616973.4	TSL:1	c.-100C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	ENSP00000477707.1
	ACP2	ENST00000672073.1	MANE Select	c.86G>A	p.Arg29Gln	missense	Exon 1 of 11	ENSP00000500291.1
	ACP2	ENST00000256997.9	TSL:1	c.86G>A	p.Arg29Gln	missense	Exon 1 of 11	ENSP00000256997.3

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

GnomAD2 exomes AF: 0.392 AC: 95049 AN: 242358 AF XY: 0.383

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 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

African (AFR) AF: 0.573 AC: 19159 AN: 33424

American (AMR) AF: 0.426 AC: 18773 AN: 44082

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5675 AN: 26068

East Asian (EAS) AF: 0.742 AC: 29340 AN: 39548

South Asian (SAS) AF: 0.458 AC: 39129 AN: 85502

European-Finnish (FIN) AF: 0.408 AC: 21677 AN: 53072

Middle Eastern (MID) AF: 0.275 AC: 1583 AN: 5760

European-Non Finnish (NFE) AF: 0.299 AC: 332120 AN: 1110466

Other (OTH) AF: 0.344 AC: 20708 AN: 60188

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

African (AFR) AF: 0.569 AC: 23621 AN: 41488

American (AMR) AF: 0.360 AC: 5505 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 779 AN: 3472

East Asian (EAS) AF: 0.747 AC: 3858 AN: 5168

South Asian (SAS) AF: 0.463 AC: 2229 AN: 4818

European-Finnish (FIN) AF: 0.427 AC: 4521 AN: 10590

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20232 AN: 67988

Other (OTH) AF: 0.339 AC: 715 AN: 2108

Alfa AF: 0.334 Hom.: 29989

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.047	T
MetaRNN	Benign	0.0000026	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.41
ClinPred		0.034	T
GERP RS		5.7
PromoterAI		0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.041
gMVP		0.19
Mutation Taster		=206/94	polymorphism

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