11-47248762-G-A

Position:

• chr11-47248762-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001302492.2(ACP2):​c.-463C>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 0.00236 in 1,601,376 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: ACP2 NM_001302492.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.519

Genes affected

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: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]

NR1H3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046778023).
• BP6: Variant 11-47248762-G-A is Benign according to our data. Variant chr11-47248762-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 786418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACP2	NM_001610.4	c.28C>T	p.Arg10Trp	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.28C>T	p.Arg10Trp	missense_variant	1/11		NM_001610.4	ENSP00000500291.1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00236 AC: 519 AN: 219968 Hom.: 0 AF XY: 0.00228 AC XY: 273 AN XY: 119520

Gnomad AFR exome AF: 0.000317

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00222

GnomAD4 exome AF: 0.00236 AC: 3418 AN: 1449014 Hom.: 5 Cov.: 32 AF XY: 0.00234 AC XY: 1682 AN XY: 719530

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00639

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74506

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00243 Hom.: 0

Bravo AF: 0.00141

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000689 AC: 3

ESP6500EA AF: 0.00245 AC: 21

ExAC AF: 0.00266 AC: 321

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.018	N
LIST_S2	Uncertain	0.86	D;D;D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0047	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.95	N;N;N;N;N
REVEL	Benign	0.080
Sift	Uncertain	0.021	D;D;D;D;D
Sift4G	Benign	0.084	T;T;D;.;T
Polyphen		0.93	P;P;B;.;.
Vest4		0.14
MVP		0.31
MPC		0.37
ClinPred		0.067	T
GERP RS		0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.068
gMVP		0.44

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: rs41275182; hg19: chr11-47270313; COSMIC: COSV57043522; COSMIC: COSV57043522;