chr12-57136887-T-C

Variant names:

• chr12-57136887-T-C
• rs4759044
• NM_002332.3:c.68-1572T>C

Variant summary

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

The NM_002332.3(LRP1):​c.68-1572T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 151,992 control chromosomes in the GnomAD database, including 15,069 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 0.44 (15069 hom., cov: 32)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210
• Publications: 14 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.528 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.68-1572T>C		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.68-1572T>C		intron	N/A	ENSP00000243077.3	Q07954-1
	LRP1	ENST00000554174.1	TSL:1	c.68-1572T>C		intron	N/A	ENSP00000451737.1	Q6PJ72
	LRP1	ENST00000553277.5	TSL:1	c.68-1572T>C		intron	N/A	ENSP00000451449.1	Q7Z7K9

Frequencies

GnomAD3 genomes AF: 0.441 AC: 67003 AN: 151876 Hom.: 15052 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.433

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

GnomAD4 genome AF: 0.441 AC: 67064 AN: 151992 Hom.: 15069 Cov.: 32 AF XY: 0.439 AC XY: 32604 AN XY: 74290

African (AFR) AF: 0.449 AC: 18600 AN: 41400

American (AMR) AF: 0.538 AC: 8225 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1405 AN: 3472

East Asian (EAS) AF: 0.248 AC: 1283 AN: 5180

South Asian (SAS) AF: 0.390 AC: 1876 AN: 4816

European-Finnish (FIN) AF: 0.416 AC: 4396 AN: 10568

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.440 AC: 29899 AN: 67958

Other (OTH) AF: 0.430 AC: 909 AN: 2114

Alfa AF: 0.443 Hom.: 12018

Bravo AF: 0.451

Asia WGS AF: 0.364 AC: 1267 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.9
DANN	Benign	0.51
PhyloP100		-0.021
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: rs4759044; hg19: chr12-57530670;