chr12-57140687-G-A

Variant names:

• chr12-57140687-G-A
• rs1466535
• NM_002332.3:c.191-687G>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.191-687G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 152,014 control chromosomes in the GnomAD database, including 7,445 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 0.30 (7445 hom., cov: 31)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579
• Publications: 70 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 (AMR) allele frequency at 95% confidence interval = 0.399 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	NM_002332.3	MANE Select	c.191-687G>A		intron	N/A	NP_002323.2	Q07954-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	ENST00000243077.8	TSL:1 MANE Select	c.191-687G>A		intron	N/A	ENSP00000243077.3	Q07954-1
	LRP1	ENST00000554174.1	TSL:1	c.191-687G>A		intron	N/A	ENSP00000451737.1	Q6PJ72
	LRP1	ENST00000553277.5	TSL:1	c.191-687G>A		intron	N/A	ENSP00000451449.1	Q7Z7K9

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45960 AN: 151896 Hom.: 7440 Cov.: 31

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.288

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.302 AC: 45980 AN: 152014 Hom.: 7445 Cov.: 31 AF XY: 0.303 AC XY: 22521 AN XY: 74304

African (AFR) AF: 0.200 AC: 8301 AN: 41476

American (AMR) AF: 0.407 AC: 6226 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 919 AN: 3470

East Asian (EAS) AF: 0.207 AC: 1069 AN: 5170

South Asian (SAS) AF: 0.347 AC: 1672 AN: 4814

European-Finnish (FIN) AF: 0.324 AC: 3414 AN: 10542

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23448 AN: 67946

Other (OTH) AF: 0.285 AC: 601 AN: 2110

Alfa AF: 0.329 Hom.: 29288

Bravo AF: 0.305

Asia WGS AF: 0.299 AC: 1040 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	8.2
DANN	Benign	0.72
PhyloP100		0.58
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: rs1466535; hg19: chr12-57534470;