12-57201172-G-A

Variant names:

• chr12-57201172-G-A
• rs11172124
• NM_002332.3:c.10345+19G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002332.3(LRP1):​c.10345+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,612,808 control chromosomes in the GnomAD database, including 47,309 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (3811 hom., cov: 31)
  • Exomes 𝑓: 0.24 (43498 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 10 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.249 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.10345+19G>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.10345+19G>A		intron	N/A	ENSP00000243077.3
	LRP1	ENST00000555124.1	TSL:4	c.46+19G>A		intron	N/A	ENSP00000451012.1
	LRP1	ENST00000555941.1	TSL:3	n.*19G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33173 AN: 152002 Hom.: 3810 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.225 AC: 56331 AN: 250486 AF XY: 0.218

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.239 AC: 348636 AN: 1460688 Hom.: 43498 Cov.: 37 AF XY: 0.234 AC XY: 170107 AN XY: 726440

African (AFR) AF: 0.159 AC: 5320 AN: 33470

American (AMR) AF: 0.270 AC: 12080 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6493 AN: 26124

East Asian (EAS) AF: 0.123 AC: 4895 AN: 39678

South Asian (SAS) AF: 0.108 AC: 9328 AN: 86194

European-Finnish (FIN) AF: 0.271 AC: 14465 AN: 53312

Middle Eastern (MID) AF: 0.234 AC: 1350 AN: 5764

European-Non Finnish (NFE) AF: 0.253 AC: 280910 AN: 1111096

Other (OTH) AF: 0.229 AC: 13795 AN: 60346

GnomAD4 genome AF: 0.218 AC: 33188 AN: 152120 Hom.: 3811 Cov.: 31 AF XY: 0.214 AC XY: 15947 AN XY: 74358

African (AFR) AF: 0.160 AC: 6651 AN: 41502

American (AMR) AF: 0.238 AC: 3627 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 878 AN: 3472

East Asian (EAS) AF: 0.133 AC: 687 AN: 5184

South Asian (SAS) AF: 0.107 AC: 518 AN: 4828

European-Finnish (FIN) AF: 0.259 AC: 2739 AN: 10578

Middle Eastern (MID) AF: 0.250 AC: 73 AN: 292

European-Non Finnish (NFE) AF: 0.253 AC: 17169 AN: 67992

Other (OTH) AF: 0.233 AC: 492 AN: 2108

Alfa AF: 0.231 Hom.: 7334

Bravo AF: 0.220

Asia WGS AF: 0.140 AC: 489 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.6
DANN	Benign	0.30
PhyloP100		1.0
PromoterAI		-0.028	Neutral
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)		0.13		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: rs11172124; hg19: chr12-57594955; COSMIC: COSV54513329; COSMIC: COSV54513329;