Genetic Variant LRP1:c.12146-51C>G (chr12-57209032-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002332.3(LRP1):c.12146-51C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,469,804 control chromosomes in the GnomAD database, including 297,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 23674 hom., cov: 32)

Exomes 𝑓: 0.64 ( 274021 hom. )

Consequence

LRP1
NM_002332.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.153

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-57209032-C-G is Benign according to our data. Variant chr12-57209032-C-G is described in ClinVar as [Benign]. Clinvar id is 1263181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3 link	c.12146-51C>G		intron_variant	Intron 78 of 88	ENST00000243077.8	NP_002323.2	Q07954-1Q59FG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8 link	c.12146-51C>G		intron_variant	Intron 78 of 88	1	NM_002332.3	ENSP00000243077.3		Q07954-1
LRP1	ENST00000556356.1 link	n.2840-51C>G		intron_variant	Intron 6 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.534

AC:

81088

AN:

151922

Hom.:

23670

Cov.:

show subpopulations

Gnomad AFR

AF:

0.284

Gnomad AMI

AF:

0.593

Gnomad AMR

AF:

0.550

Gnomad ASJ

AF:

0.627

Gnomad EAS

AF:

0.524

Gnomad SAS

AF:

0.747

Gnomad FIN

AF:

0.592

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.652

Gnomad OTH

AF:

0.555

GnomAD3 exomes

AF:

0.592

AC:

144861

AN:

244816

Hom.:

44974

AF XY:

0.614

AC XY:

81239

AN XY:

132288

show subpopulations

Gnomad AFR exome

AF:

0.273

Gnomad AMR exome

AF:

0.443

Gnomad ASJ exome

AF:

0.630

Gnomad EAS exome

AF:

0.525

Gnomad SAS exome

AF:

0.763

Gnomad FIN exome

AF:

0.580

Gnomad NFE exome

AF:

0.647

Gnomad OTH exome

AF:

0.616

GnomAD4 exome

AF:

0.639

AC:

841972

AN:

1317764

Hom.:

274021

Cov.:

AF XY:

0.646

AC XY:

424849

AN XY:

657838

show subpopulations

Gnomad4 AFR exome

AF:

0.265

Gnomad4 AMR exome

AF:

0.453

Gnomad4 ASJ exome

AF:

0.633

Gnomad4 EAS exome

AF:

0.575

Gnomad4 SAS exome

AF:

0.760

Gnomad4 FIN exome

AF:

0.584

Gnomad4 NFE exome

AF:

0.655

Gnomad4 OTH exome

AF:

0.622

GnomAD4 genome

AF:

0.533

AC:

81101

AN:

152040

Hom.:

23674

Cov.:

AF XY:

0.536

AC XY:

39819

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.283

Gnomad4 AMR

AF:

0.549

Gnomad4 ASJ

AF:

0.627

Gnomad4 EAS

AF:

0.526

Gnomad4 SAS

AF:

0.747

Gnomad4 FIN

AF:

0.592

Gnomad4 NFE

AF:

0.652

Gnomad4 OTH

AF:

0.557

Alfa

AF:

0.545

Hom.:

3390

Bravo

AF:

0.507

Asia WGS

AF:

0.556

AC:

1936

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

-0.83

CADD

Benign

0.86

DANN

Benign

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over