Genetic Variant LRP8:p.Arg736Gln (chr1-53258321-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004631.5(LRP8):c.2207G>A(p.Arg736Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000737 in 1,613,604 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0037 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 4 hom. )

Consequence

LRP8
NM_004631.5 missense, splice_region

Scores

Splicing: ADA: 0.3690

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.81

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 links:

LOC105378728 (HGNC:):

LOC105378728 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061583817).

BP6

Variant 1-53258321-C-T is Benign according to our data. Variant chr1-53258321-C-T is described in ClinVar as [Benign]. Clinvar id is 711273.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 565 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP8	NM_004631.5 link	c.2207G>A	p.Arg736Gln	missense_variant, splice_region_variant	Exon 14 of 19	ENST00000306052.12	NP_004622.2	Q14114-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12 link	c.2207G>A	p.Arg736Gln	missense_variant, splice_region_variant	Exon 14 of 19	1	NM_004631.5	ENSP00000303634.6		Q14114-1

Frequencies

GnomAD3 genomes

AF:

0.00369

AC:

561

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00103

AC:

257

AN:

250184

Hom.:

AF XY:

0.000799

AC XY:

108

AN XY:

135156

show subpopulations

Gnomad AFR exome

AF:

0.0133

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.0000798

Gnomad OTH exome

AF:

0.000984

GnomAD4 exome

AF:

0.000427

AC:

624

AN:

1461274

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

273

AN XY:

726964

show subpopulations

Gnomad4 AFR exome

AF:

0.0129

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000738

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00371

AC:

565

AN:

152330

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

256

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0129

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000577

Hom.:

Bravo

AF:

0.00384

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00124

AC:

151

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

T;.;.;.;.

Eigen

Benign

0.061

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.89

D;D;.;T;D

MetaRNN

Benign

0.0036

T;T;T;T;T

MetaSVM

Uncertain

0.016

MutationAssessor

Benign

1.4

L;L;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.76

N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.17

T;T;T;T;T

Sift4G

Benign

0.47

T;T;T;T;T

Polyphen

0.22

B;D;B;D;B

Vest4

0.10

MVP

0.73

MPC

0.53

ClinPred

0.0082

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.37

dbscSNV1_RF

Benign

0.43

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