chr12-57145299-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

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

Publications

31 publications found

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 Unknown,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002332.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	NM_002332.3	MANE Select	c.650C>T	p.Ala217Val	missense	Exon 6 of 89	NP_002323.2
	LRP1-AS	NR_131938.2	MANE Select	n.182-216G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRP1	ENST00000243077.8	TSL:1 MANE Select	c.650C>T	p.Ala217Val	missense	Exon 6 of 89	ENSP00000243077.3
LRP1	ENST00000554174.1	TSL:1	c.650C>T	p.Ala217Val	missense	Exon 6 of 8	ENSP00000451737.1
LRP1	ENST00000553277.5	TSL:1	c.650C>T	p.Ala217Val	missense	Exon 6 of 7	ENSP00000451449.1

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

GnomAD2 exomes

AF:

0.0181

AC:

4538

AN:

251278

AF XY:

0.0184

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 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

African (AFR)

AF:

0.00230

AC:

AN:

33480

American (AMR)

AF:

0.00874

AC:

391

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00854

AC:

737

AN:

86256

European-Finnish (FIN)

AF:

0.0479

AC:

2556

AN:

53404

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0244

AC:

27101

AN:

1111996

Other (OTH)

AF:

0.0171

AC:

1032

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1967

3934

5900

7867

9834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

956

1912

2868

3824

4780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0179

AC:

2726

AN:

152272

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1410

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00310

AC:

129

AN:

41560

American (AMR)

AF:

0.0178

AC:

272

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0520

AC:

552

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0250

AC:

1700

AN:

68016

Other (OTH)

AF:

0.0152

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

129

259

388

518

647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0203

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

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

-0.056

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.1

PhyloP100

1.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

REVEL

Benign

0.26

Sift

Uncertain

0.019

Sift4G

Uncertain

0.023

Polyphen

0.0010

Vest4

0.26

ClinPred

0.013

GERP RS

4.2

Varity_R

0.13

gMVP

0.28

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over