rs1800164

Positions:

• chr12-57211019-A-G
• chr12-57211019-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002332.3(LRP1):​c.12916+140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,378,820 control chromosomes in the GnomAD database, including 278,852 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22910 hom., cov: 33)
  • Exomes 𝑓: 0.64 (255942 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0810

Genes affected

LRP1 (HGNC:6692): (LDL receptor related protein 1) This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer's disease patients. [provided by RefSeq, Oct 2015]

LRP1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-57211019-A-G is Benign according to our data. Variant chr12-57211019-A-G is described in ClinVar as [Benign]. Clinvar id is 1251016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP1	NM_002332.3	c.12916+140A>G		intron_variant		ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.12916+140A>G		intron_variant		1	NM_002332.3	ENSP00000243077.3
LRP1	ENST00000556356.1	n.3610+140A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78300 AN: 152022 Hom.: 22906 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.536

GnomAD4 exome AF: 0.640 AC: 784470 AN: 1226680 Hom.: 255942 Cov.: 18 AF XY: 0.646 AC XY: 389885 AN XY: 603956

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.457

Gnomad4 ASJ exome AF: 0.634

Gnomad4 EAS exome AF: 0.579

Gnomad4 SAS exome AF: 0.759

Gnomad4 FIN exome AF: 0.582

Gnomad4 NFE exome AF: 0.656

Gnomad4 OTH exome AF: 0.617

GnomAD4 genome AF: 0.515 AC: 78305 AN: 152140 Hom.: 22910 Cov.: 33 AF XY: 0.518 AC XY: 38542 AN XY: 74384

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.626

Gnomad4 EAS AF: 0.524

Gnomad4 SAS AF: 0.745

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.652

Gnomad4 OTH AF: 0.538

Alfa AF: 0.625 Hom.: 21654

Bravo AF: 0.486

Asia WGS AF: 0.549 AC: 1910 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1800164; hg19: chr12-57604802; COSMIC: COSV54505337;