12-57211019-A-G

Variant names:

• chr12-57211019-A-G
• rs1800164
• NM_002332.3:c.12916+140A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• keratosis follicularis spinulosa decalvans

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrophoderma vermiculata

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• developmental dysplasia of the hip 3

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• keratosis pilaris atrophicans

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• schizophrenia

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002332.3. 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
	LRP1	NM_002332.3	MANE Select	c.12916+140A>G		intron	N/A	NP_002323.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	ENST00000243077.8	TSL:1 MANE Select	c.12916+140A>G		intron	N/A	ENSP00000243077.3
	LRP1	ENST00000556356.1	TSL:2	n.3610+140A>G		intron	N/A

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

African (AFR) AF: 0.201 AC: 5701 AN: 28310

American (AMR) AF: 0.457 AC: 14188 AN: 31042

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 12760 AN: 20132

East Asian (EAS) AF: 0.579 AC: 20739 AN: 35796

South Asian (SAS) AF: 0.759 AC: 52077 AN: 68608

European-Finnish (FIN) AF: 0.582 AC: 20790 AN: 35728

Middle Eastern (MID) AF: 0.585 AC: 2866 AN: 4902

European-Non Finnish (NFE) AF: 0.656 AC: 623350 AN: 950312

Other (OTH) AF: 0.617 AC: 31999 AN: 51850

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

African (AFR) AF: 0.220 AC: 9139 AN: 41508

American (AMR) AF: 0.540 AC: 8259 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2174 AN: 3472

East Asian (EAS) AF: 0.524 AC: 2709 AN: 5166

South Asian (SAS) AF: 0.745 AC: 3601 AN: 4832

European-Finnish (FIN) AF: 0.591 AC: 6265 AN: 10594

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44315 AN: 67962

Other (OTH) AF: 0.538 AC: 1133 AN: 2106

Alfa AF: 0.598 Hom.: 26842

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.62
PhyloP100		0.081
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800164; hg19: chr12-57604802; COSMIC: COSV54505337;