12-57147065-C-G

Variant names:

• chr12-57147065-C-G
• rs7398375
• NM_002332.3:c.841+1575C>G

Variant summary

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

The NM_002332.3(LRP1):​c.841+1575C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 151,694 control chromosomes in the GnomAD database, including 5,542 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 0.26 (5542 hom., cov: 31)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0960
• Publications: 13 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-AS (HGNC:51694): (LRP1 antisense RNA)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.841+1575C>G		intron_variant	Intron 6 of 88	ENST00000243077.8	NP_002323.2
LRP1-AS	NR_131938.2	n.181+374G>C		intron_variant	Intron 1 of 1
LRP1-AS	NR_131939.2	n.182-342G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.841+1575C>G		intron_variant	Intron 6 of 88	1	NM_002332.3	ENSP00000243077.3

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39643 AN: 151576 Hom.: 5538 Cov.: 31

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.270

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

GnomAD4 genome AF: 0.261 AC: 39660 AN: 151694 Hom.: 5542 Cov.: 31 AF XY: 0.267 AC XY: 19762 AN XY: 74138

African (AFR) AF: 0.172 AC: 7101 AN: 41354

American (AMR) AF: 0.266 AC: 4061 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 708 AN: 3470

East Asian (EAS) AF: 0.527 AC: 2701 AN: 5128

South Asian (SAS) AF: 0.362 AC: 1737 AN: 4792

European-Finnish (FIN) AF: 0.332 AC: 3506 AN: 10546

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.277 AC: 18799 AN: 67834

Other (OTH) AF: 0.274 AC: 576 AN: 2104

Alfa AF: 0.263 Hom.: 640

Bravo AF: 0.257

Asia WGS AF: 0.378 AC: 1312 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.9
DANN	Benign	0.70
PhyloP100		-0.096
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: rs7398375; hg19: chr12-57540848;