12-57145299-C-T

Position:

chr12-57145299-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_002332.3(LRP1):c.650C>T(p.Ala217Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,614,124 control chromosomes in the GnomAD database, including 462 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.018 ( 38 hom., cov: 32)

Exomes 𝑓: 0.022 ( 424 hom. )

Consequence

LRP1
NM_002332.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.19

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:

LRP1-AS (HGNC:51694): (LRP1 antisense RNA)

LRP1-AS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP1. . Gene score misZ 8.2463 (greater than the threshold 3.09). Trascript score misZ 12.011 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia, atrophoderma vermiculata, keratosis pilaris atrophicans, keratosis follicularis spinulosa decalvans.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045386255).

BP6

Variant 12-57145299-C-T is Benign according to our data. Variant chr12-57145299-C-T is described in ClinVar as [Benign]. Clinvar id is 3042317.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2726/152272) while in subpopulation NFE AF= 0.025 (1700/68016). AF 95% confidence interval is 0.024. There are 38 homozygotes in gnomad4. There are 1410 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 38 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3 linkuse as main transcript	c.650C>T	p.Ala217Val	missense_variant	6/89	ENST00000243077.8
LRP1-AS	NR_131938.1 linkuse as main transcript	n.182-216G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8 linkuse as main transcript	c.650C>T	p.Ala217Val	missense_variant	6/89	1	NM_002332.3	P1	Q07954-1
LRP1-AS	ENST00000555461.1 linkuse as main transcript	n.182-216G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2728

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00311

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0520

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0250

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0181

AC:

4538

AN:

251278

Hom.:

AF XY:

0.0184

AC XY:

2495

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00816

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00905

Gnomad FIN exome

AF:

0.0501

Gnomad NFE exome

AF:

0.0243

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0219

AC:

31961

AN:

1461852

Hom.:

424

Cov.:

AF XY:

0.0218

AC XY:

15835

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00230

Gnomad4 AMR exome

AF:

0.00874

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00854

Gnomad4 FIN exome

AF:

0.0479

Gnomad4 NFE exome

AF:

0.0244

Gnomad4 OTH exome

AF:

0.0171

GnomAD4 genome

AF:

0.0179

AC:

2726

AN:

152272

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1410

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00310

Gnomad4 AMR

AF:

0.0178

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00622

Gnomad4 FIN

AF:

0.0520

Gnomad4 NFE

AF:

0.0250

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0241

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0222

AC:

191

ExAC

AF:

0.0176

AC:

2133

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0212

EpiControl

AF:

0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

LRP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;T;.;T

Eigen

Benign

-0.056

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

D;D;D;D

MetaRNN

Benign

0.0045

T;T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.1

.;L;L;.

MutationTaster

Benign

0.83

N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.019

D;D;D;D

Sift4G

Uncertain

0.023

D;D;D;D

Polyphen

0.0010

B;B;.;B

Vest4

0.26

ClinPred

0.013

GERP RS

4.2

Varity_R

0.13

gMVP

0.28

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