12-57173979-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002332.3(LRP1):c.3546C>T(p.Cys1182=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,613,108 control chromosomes in the GnomAD database, including 89,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11279 hom., cov: 33)

Exomes 𝑓: 0.32 ( 77918 hom. )

Consequence

LRP1
NM_002332.3 splice_region, synonymous

Scores

Splicing: ADA: 0.0007581

Clinical Significance

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

Conservation

PhyloP100: -0.348

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-57173979-C-T is Benign according to our data. Variant chr12-57173979-C-T is described in ClinVar as [Benign]. Clinvar id is 1226322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57173979-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.348 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3 linkuse as main transcript	c.3546C>T	p.Cys1182=	splice_region_variant, synonymous_variant	22/89	ENST00000243077.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8 linkuse as main transcript	c.3546C>T	p.Cys1182=	splice_region_variant, synonymous_variant	22/89	1	NM_002332.3	P1	Q07954-1

Frequencies

GnomAD3 genomes

AF:

0.375

AC:

57025

AN:

151936

Hom.:

11253

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.392

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.394

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.314

Gnomad OTH

AF:

0.366

GnomAD3 exomes

AF:

0.355

AC:

88789

AN:

250136

Hom.:

16991

AF XY:

0.337

AC XY:

45562

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.487

Gnomad AMR exome

AF:

0.512

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.390

Gnomad SAS exome

AF:

0.210

Gnomad FIN exome

AF:

0.407

Gnomad NFE exome

AF:

0.318

Gnomad OTH exome

AF:

0.336

GnomAD4 exome

AF:

0.321

AC:

468503

AN:

1461054

Hom.:

77918

Cov.:

AF XY:

0.315

AC XY:

228846

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.485

Gnomad4 AMR exome

AF:

0.500

Gnomad4 ASJ exome

AF:

0.304

Gnomad4 EAS exome

AF:

0.362

Gnomad4 SAS exome

AF:

0.211

Gnomad4 FIN exome

AF:

0.400

Gnomad4 NFE exome

AF:

0.312

Gnomad4 OTH exome

AF:

0.325

GnomAD4 genome

AF:

0.375

AC:

57090

AN:

152054

Hom.:

11279

Cov.:

AF XY:

0.374

AC XY:

27800

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.485

Gnomad4 AMR

AF:

0.393

Gnomad4 ASJ

AF:

0.310

Gnomad4 EAS

AF:

0.398

Gnomad4 SAS

AF:

0.230

Gnomad4 FIN

AF:

0.394

Gnomad4 NFE

AF:

0.314

Gnomad4 OTH

AF:

0.362

Alfa

AF:

0.330

Hom.:

14671

Bravo

AF:

0.391

Asia WGS

AF:

0.372

AC:

1294

AN:

3478

EpiCase

AF:

0.303

EpiControl

AF:

0.308

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Keratosis pilaris

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 12732394) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

Cadd

Benign

Dann

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00076

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.040

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