Variant rs5174 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004631.5(LRP8):c.2855G>T(p.Arg952Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LRP8
NM_004631.5 missense, splice_region

Scores

Splicing: ADA: 0.9750

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.18

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP8	NM_004631.5 link	c.2855G>T	p.Arg952Leu	missense_variant, splice_region_variant	Exon 19 of 19	ENST00000306052.12	NP_004622.2	Q14114-1
LRP8	NM_001018054.3 link	c.2678G>T	p.Arg893Leu	missense_variant, splice_region_variant	Exon 18 of 18		NP_001018064.1	Q14114-3
LRP8	NM_033300.4 link	c.2345G>T	p.Arg782Leu	missense_variant, splice_region_variant	Exon 17 of 17		NP_150643.2	Q14114-4
LRP8	NM_017522.5 link	c.2066G>T	p.Arg689Leu	missense_variant, splice_region_variant	Exon 16 of 16		NP_059992.3	Q14114-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12 link	c.2855G>T	p.Arg952Leu	missense_variant, splice_region_variant	Exon 19 of 19	1	NM_004631.5	ENSP00000303634.6		Q14114-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717630

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

T;.;.;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

T;T;.;T;T

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.50

T;D;D;D;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

0.69

N;.;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.53

N;D;D;N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0040

D;T;T;T;D

Sift4G

Pathogenic

0.0

D;T;T;T;D

Polyphen

1.0

D;B;P;D;D

Vest4

0.59

MutPred

0.27

Gain of sheet (P = 0.0344);.;.;.;.;

MVP

0.95

MPC

1.1

ClinPred

0.84

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.71

SpliceAI score (max)

0.060

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over