1-53247055-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3BA1

The NM_004631.5(LRP8):c.2855G>A(p.Arg952Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.356 in 1,591,796 control chromosomes in the GnomAD database, including 112,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.28 ( 7722 hom., cov: 32)

Exomes 𝑓: 0.36 ( 104345 hom. )

Consequence

LRP8
NM_004631.5 missense, splice_region

Scores

Splicing: ADA: 0.9742

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 7.18

Publications

82 publications found

Variant links:

Genes affected

LRP8 (HGNC:6700): (LDL receptor related protein 8) This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

LRP8 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

LRP8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004631.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP8	NM_004631.5	MANE Select	c.2855G>A	p.Arg952Gln	missense splice_region	Exon 19 of 19	NP_004622.2	Q14114-1
LRP8	NM_001018054.3		c.2678G>A	p.Arg893Gln	missense splice_region	Exon 18 of 18	NP_001018064.1	Q14114-3
LRP8	NM_033300.4		c.2345G>A	p.Arg782Gln	missense splice_region	Exon 17 of 17	NP_150643.2	Q14114-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP8	ENST00000306052.12	TSL:1 MANE Select	c.2855G>A	p.Arg952Gln	missense splice_region	Exon 19 of 19	ENSP00000303634.6	Q14114-1
LRP8	ENST00000371454.6	TSL:1	c.2678G>A	p.Arg893Gln	missense splice_region	Exon 18 of 18	ENSP00000360509.2	Q14114-3
LRP8	ENST00000347547.7	TSL:1	c.2345G>A	p.Arg782Gln	missense splice_region	Exon 17 of 17	ENSP00000334522.2	Q14114-4

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42102

AN:

151976

Hom.:

7720

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0721

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.251

Gnomad ASJ

AF:

0.296

Gnomad EAS

AF:

0.0328

Gnomad SAS

AF:

0.166

Gnomad FIN

AF:

0.432

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.408

Gnomad OTH

AF:

0.247

GnomAD2 exomes

AF:

0.292

AC:

66973

AN:

229590

AF XY:

0.296

show subpopulations

Gnomad AFR exome

AF:

0.0647

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.294

Gnomad EAS exome

AF:

0.0310

Gnomad FIN exome

AF:

0.427

Gnomad NFE exome

AF:

0.401

Gnomad OTH exome

AF:

0.305

GnomAD4 exome

AF:

0.365

AC:

524945

AN:

1439702

Hom.:

104345

Cov.:

AF XY:

0.361

AC XY:

258129

AN XY:

715976

show subpopulations

African (AFR)

AF:

0.0559

AC:

1819

AN:

32560

American (AMR)

AF:

0.192

AC:

7602

AN:

39568

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

7480

AN:

25578

East Asian (EAS)

AF:

0.0396

AC:

1558

AN:

39302

South Asian (SAS)

AF:

0.170

AC:

13915

AN:

82074

European-Finnish (FIN)

AF:

0.423

AC:

22529

AN:

53200

Middle Eastern (MID)

AF:

0.219

AC:

1259

AN:

5738

European-Non Finnish (NFE)

AF:

0.408

AC:

449682

AN:

1102030

Other (OTH)

AF:

0.320

AC:

19101

AN:

59652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

14157

28313

42470

56626

70783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13428

26856

40284

53712

67140

<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:

0.277

AC:

42103

AN:

152094

Hom.:

7722

Cov.:

AF XY:

0.274

AC XY:

20355

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0720

AC:

2986

AN:

41500

American (AMR)

AF:

0.251

AC:

3833

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

1027

AN:

3472

East Asian (EAS)

AF:

0.0330

AC:

171

AN:

5178

South Asian (SAS)

AF:

0.166

AC:

801

AN:

4822

European-Finnish (FIN)

AF:

0.432

AC:

4577

AN:

10586

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.408

AC:

27697

AN:

67944

Other (OTH)

AF:

0.250

AC:

527

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1372

2744

4115

5487

6859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.359

Hom.:

49998

Bravo

AF:

0.253

TwinsUK

AF:

0.402

AC:

1490

ALSPAC

AF:

0.411

AC:

1584

ESP6500AA

AF:

0.0828

AC:

365

ESP6500EA

AF:

0.395

AC:

3401

ExAC

AF:

0.294

AC:

35749

Asia WGS

AF:

0.121

AC:

424

AN:

3478

ClinVar

ClinVar submissions

Significance:risk factor

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myocardial infarction, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.049

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.69

PhyloP100

7.2

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.29

REVEL

Uncertain

0.39

Sift

Benign

0.049

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.45

MPC

1.2

ClinPred

0.033

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.18

Mutation Taster

=64/36

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.82

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over