rs9669595

Variant names:

• chr12-57201283-G-A
• rs9669595
• NM_002332.3:c.10345+130G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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 -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 VariationId 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 rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.10345+130G>A		intron_variant	Intron 65 of 88	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.10345+130G>A		intron_variant	Intron 65 of 88	1	NM_002332.3	ENSP00000243077.3
LRP1	ENST00000555124.1	c.46+130G>A		intron_variant	Intron 1 of 4	4		ENSP00000451012.1
LRP1	ENST00000555941.1	n.*130G>A		downstream_gene_variant		3

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

African (AFR) AF: 0.502 AC: 14801 AN: 29474

American (AMR) AF: 0.343 AC: 12104 AN: 35258

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 7260 AN: 21234

East Asian (EAS) AF: 0.331 AC: 12613 AN: 38144

South Asian (SAS) AF: 0.209 AC: 14962 AN: 71730

European-Finnish (FIN) AF: 0.414 AC: 19518 AN: 47096

Middle Eastern (MID) AF: 0.377 AC: 1986 AN: 5268

European-Non Finnish (NFE) AF: 0.321 AC: 311972 AN: 972136

Other (OTH) AF: 0.334 AC: 17921 AN: 53634

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

African (AFR) AF: 0.505 AC: 20920 AN: 41412

American (AMR) AF: 0.335 AC: 5120 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1232 AN: 3470

East Asian (EAS) AF: 0.367 AC: 1895 AN: 5166

South Asian (SAS) AF: 0.220 AC: 1064 AN: 4830

European-Finnish (FIN) AF: 0.406 AC: 4293 AN: 10584

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22551 AN: 67956

Other (OTH) AF: 0.369 AC: 780 AN: 2114

Alfa AF: 0.356 Hom.: 2091

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.33
PhyloP100		-0.26
PromoterAI		0.0076	Neutral
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: rs9669595; hg19: chr12-57595066; COSMIC: COSV107290457; COSMIC: COSV107290457;