rs4759044

Positions:

• chr12-57136887-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP1	NM_002332.3	c.68-1572T>C		intron_variant		ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.68-1572T>C		intron_variant		1	NM_002332.3	ENSP00000243077.3
LRP1	ENST00000554174.1	c.68-1572T>C		intron_variant		1		ENSP00000451737.1
LRP1	ENST00000553277.5	c.68-1572T>C		intron_variant		1		ENSP00000451449.1
LRP1	ENST00000338962.8	c.68-1572T>C		intron_variant		1		ENSP00000341264.4

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

Gnomad4 AFR AF: 0.449

Gnomad4 AMR AF: 0.538

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.390

Gnomad4 FIN AF: 0.416

Gnomad4 NFE AF: 0.440

Gnomad4 OTH AF: 0.430

Alfa AF: 0.442 Hom.: 10094

Bravo AF: 0.451

Asia WGS AF: 0.364 AC: 1267 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.9
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs4759044; hg19: chr12-57530670;