12-57184505-C-T

Variant names:

• chr12-57184505-C-T
• rs1800181
• NM_002332.3:c.6186+53C>T

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.6186+53C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,607,578 control chromosomes in the GnomAD database, including 88,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11135 hom., cov: 32)
  • Exomes 𝑓: 0.32 (77775 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0170
• Publications: 15 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=-0.86).
• BP6: Variant 12-57184505-C-T is Benign according to our data. Variant chr12-57184505-C-T is described in ClinVar as Benign. ClinVar VariationId is 1230367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.6186+53C>T		intron_variant	Intron 38 of 88	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.6186+53C>T		intron_variant	Intron 38 of 88	1	NM_002332.3	ENSP00000243077.3

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56797 AN: 151976 Hom.: 11119 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.365

GnomAD4 exome AF: 0.321 AC: 467728 AN: 1455484 Hom.: 77775 AF XY: 0.316 AC XY: 228394 AN XY: 723694

African (AFR) AF: 0.476 AC: 15895 AN: 33364

American (AMR) AF: 0.502 AC: 22161 AN: 44116

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7871 AN: 25914

East Asian (EAS) AF: 0.366 AC: 14477 AN: 39546

South Asian (SAS) AF: 0.213 AC: 18244 AN: 85614

European-Finnish (FIN) AF: 0.400 AC: 21055 AN: 52644

Middle Eastern (MID) AF: 0.325 AC: 1698 AN: 5218

European-Non Finnish (NFE) AF: 0.313 AC: 346798 AN: 1108962

Other (OTH) AF: 0.325 AC: 19529 AN: 60106

GnomAD4 genome AF: 0.374 AC: 56846 AN: 152094 Hom.: 11135 Cov.: 32 AF XY: 0.372 AC XY: 27677 AN XY: 74332

African (AFR) AF: 0.476 AC: 19758 AN: 41468

American (AMR) AF: 0.394 AC: 6018 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1075 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2094 AN: 5178

South Asian (SAS) AF: 0.232 AC: 1117 AN: 4822

European-Finnish (FIN) AF: 0.394 AC: 4167 AN: 10588

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21368 AN: 67966

Other (OTH) AF: 0.361 AC: 762 AN: 2110

Alfa AF: 0.340 Hom.: 1860

Bravo AF: 0.389

Asia WGS AF: 0.377 AC: 1309 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.9
DANN	Benign	0.50
PhyloP100		0.017
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800181; hg19: chr12-57578288; COSMIC: COSV54514398; COSMIC: COSV54514398;