rs11837145

Variant names:

• chr12-57176231-C-A
• rs11837145
• NM_002332.3:c.3991+125C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_002332.3(LRP1):​c.3991+125C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 886,292 control chromosomes in the GnomAD database, including 50,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (11442 hom., cov: 33)
  • Exomes 𝑓: 0.32 (38791 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.58
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 12-57176231-C-A is Benign according to our data. Variant chr12-57176231-C-A is described in ClinVar as Benign. ClinVar VariationId is 1260371.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 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.3991+125C>A		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.3991+125C>A		intron	N/A	ENSP00000243077.3

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57423 AN: 152096 Hom.: 11414 Cov.: 33

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.368

GnomAD4 exome AF: 0.317 AC: 232547 AN: 734076 Hom.: 38791 AF XY: 0.311 AC XY: 117243 AN XY: 376984

African (AFR) AF: 0.480 AC: 8597 AN: 17898

American (AMR) AF: 0.461 AC: 10187 AN: 22088

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 4882 AN: 16248

East Asian (EAS) AF: 0.400 AC: 13396 AN: 33452

South Asian (SAS) AF: 0.212 AC: 11834 AN: 55716

European-Finnish (FIN) AF: 0.397 AC: 13275 AN: 33438

Middle Eastern (MID) AF: 0.301 AC: 777 AN: 2580

European-Non Finnish (NFE) AF: 0.305 AC: 157780 AN: 517062

Other (OTH) AF: 0.332 AC: 11819 AN: 35594

GnomAD4 genome AF: 0.378 AC: 57496 AN: 152216 Hom.: 11442 Cov.: 33 AF XY: 0.377 AC XY: 28039 AN XY: 74424

African (AFR) AF: 0.486 AC: 20164 AN: 41528

American (AMR) AF: 0.393 AC: 6008 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1074 AN: 3464

East Asian (EAS) AF: 0.452 AC: 2344 AN: 5182

South Asian (SAS) AF: 0.232 AC: 1118 AN: 4828

European-Finnish (FIN) AF: 0.394 AC: 4176 AN: 10594

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

European-Non Finnish (NFE) AF: 0.314 AC: 21350 AN: 68000

Other (OTH) AF: 0.367 AC: 775 AN: 2112

Alfa AF: 0.339 Hom.: 11373

Bravo AF: 0.394

Asia WGS AF: 0.412 AC: 1432 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.44
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs11837145; hg19: chr12-57570014;