rs9669595

Positions:

• chr12-57201283-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002332.3(LRP1):​c.10345+130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,425,992 control chromosomes in the GnomAD database, including 81,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11760 hom., cov: 31)
  • Exomes 𝑓: 0.32 (69343 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.264

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-57201283-G-A is Benign according to our data. Variant chr12-57201283-G-A is described in ClinVar as [Benign]. Clinvar id is 1289136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3	c.10345+130G>A		intron_variant		ENST00000243077.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8	c.10345+130G>A		intron_variant		1	NM_002332.3	P1
LRP1	ENST00000555124.1	c.46+130G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58311 AN: 151900 Hom.: 11743 Cov.: 31

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.373

GnomAD4 exome AF: 0.324 AC: 413137 AN: 1273974 Hom.: 69343 AF XY: 0.320 AC XY: 201571 AN XY: 630336

Gnomad4 AFR exome AF: 0.502

Gnomad4 AMR exome AF: 0.343

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.331

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.414

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.384 AC: 58357 AN: 152018 Hom.: 11760 Cov.: 31 AF XY: 0.381 AC XY: 28323 AN XY: 74308

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.355

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.369

Alfa AF: 0.352 Hom.: 1991

Bravo AF: 0.391

Asia WGS AF: 0.327 AC: 1135 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.33

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: rs9669595; hg19: chr12-57595066;