rs7975818

chr12-57164722-G-Cchr12-57164722-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002332.3(LRP1):c.2531-1083G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 152,064 control chromosomes in the GnomAD database, including 17,945 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 0.45 (17944 hom., cov: 33)
  • Exomes 𝑓: 0.67 (1 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153

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 (AFR) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3	c.2531-1083G>C		intron_variant		ENST00000243077.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8	c.2531-1083G>C		intron_variant		1	NM_002332.3	P1
LRP1	ENST00000556830.1	n.295G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68365 AN: 151940 Hom.: 17892 Cov.: 33

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.414

GnomAD4 exome AF: 0.667 AC: 4 AN: 6 Hom.: 1 Cov.: 0 AF XY: 0.750 AC XY: 3 AN XY: 4

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.450 AC: 68472 AN: 152058 Hom.: 17944 Cov.: 33 AF XY: 0.447 AC XY: 33248 AN XY: 74312

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.461

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.412

Alfa AF: 0.208 Hom.: 430

Bravo AF: 0.476

Asia WGS AF: 0.432 AC: 1500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	5.0
Dann	Benign	0.46

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: rs7975818; hg19: chr12-57558505;