12-57141483-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_002332.3(LRP1):c.300C>T(p.Asp100Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,992 control chromosomes in the GnomAD database, including 17,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.12 ( 1265 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15953 hom. )

Consequence

LRP1
NM_002332.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: -2.02

Publications

117 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 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)

LRP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP7

Synonymous conserved (PhyloP=-2.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3 link	c.300C>T	p.Asp100Asp	synonymous_variant	Exon 3 of 89	ENST00000243077.8	NP_002323.2	Q07954-1Q59FG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP1	ENST00000243077.8 link	c.300C>T	p.Asp100Asp	synonymous_variant	Exon 3 of 89	1	NM_002332.3	ENSP00000243077.3	Q07954-1
LRP1	ENST00000554174.1 link	c.300C>T	p.Asp100Asp	synonymous_variant	Exon 3 of 8	1		ENSP00000451737.1	Q6PJ72
LRP1	ENST00000553277.5 link	c.300C>T	p.Asp100Asp	synonymous_variant	Exon 3 of 7	1		ENSP00000451449.1	Q7Z7K9
LRP1	ENST00000338962.8 link	c.300C>T	p.Asp100Asp	synonymous_variant	Exon 3 of 7	1		ENSP00000341264.4	Q07954-2

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18129

AN:

152128

Hom.:

1262

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0592

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.0866

Gnomad ASJ

AF:

0.223

Gnomad EAS

AF:

0.0668

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.184

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.133

GnomAD2 exomes

AF:

0.129

AC:

32334

AN:

251146

AF XY:

0.134

show subpopulations

Gnomad AFR exome

AF:

0.0525

Gnomad AMR exome

AF:

0.0653

Gnomad ASJ exome

AF:

0.217

Gnomad EAS exome

AF:

0.0555

Gnomad FIN exome

AF:

0.176

Gnomad NFE exome

AF:

0.148

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.144

AC:

210412

AN:

1461746

Hom.:

15953

Cov.:

AF XY:

0.145

AC XY:

105732

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.0531

AC:

1777

AN:

33478

American (AMR)

AF:

0.0677

AC:

3026

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

5751

AN:

26136

East Asian (EAS)

AF:

0.0821

AC:

3261

AN:

39700

South Asian (SAS)

AF:

0.150

AC:

12945

AN:

86250

European-Finnish (FIN)

AF:

0.172

AC:

9165

AN:

53414

Middle Eastern (MID)

AF:

0.178

AC:

1027

AN:

5768

European-Non Finnish (NFE)

AF:

0.148

AC:

165115

AN:

1111882

Other (OTH)

AF:

0.138

AC:

8345

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

9301

18603

27904

37206

46507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5848

11696

17544

23392

29240

<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:

0.119

AC:

18129

AN:

152246

Hom.:

1265

Cov.:

AF XY:

0.123

AC XY:

9132

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0592

AC:

2461

AN:

41568

American (AMR)

AF:

0.0865

AC:

1324

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

773

AN:

3472

East Asian (EAS)

AF:

0.0670

AC:

347

AN:

5182

South Asian (SAS)

AF:

0.136

AC:

653

AN:

4818

European-Finnish (FIN)

AF:

0.184

AC:

1952

AN:

10592

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.150

AC:

10205

AN:

67996

Other (OTH)

AF:

0.131

AC:

277

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

826

1652

2479

3305

4131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

206

412

618

824

1030

<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:

0.140

Hom.:

5011

Bravo

AF:

0.107

Asia WGS

AF:

0.0970

AC:

337

AN:

3478

EpiCase

AF:

0.153

EpiControl

AF:

0.153

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22819221, 12732394, 28924541, 11076057, 9633759) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Keratosis pilaris

Pathogenic:1

Jan 01, 2019

Endocrine Laboratory of Southeast University, Southeast University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

early diagnosis and prevention on AD -

Keratosis pilaris atrophicans;C5882750:Developmental dysplasia of the hip 3

Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

LRP1-related disorder

Benign:1

Dec 07, 2023

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

4.1

(source)

DANN

Benign

0.88

PhyloP100

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over