dbSNP rs5174: LRP8:p.Arg952Leu (chr1-53247055-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as (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: 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

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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>T	p.Arg952Leu	missense splice_region	Exon 19 of 19	NP_004622.2	Q14114-1
LRP8	NM_001018054.3		c.2678G>T	p.Arg893Leu	missense splice_region	Exon 18 of 18	NP_001018064.1	Q14114-3
LRP8	NM_033300.4		c.2345G>T	p.Arg782Leu	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>T	p.Arg952Leu	missense splice_region	Exon 19 of 19	ENSP00000303634.6	Q14114-1
LRP8	ENST00000371454.6	TSL:1	c.2678G>T	p.Arg893Leu	missense splice_region	Exon 18 of 18	ENSP00000360509.2	Q14114-3
LRP8	ENST00000347547.7	TSL:1	c.2345G>T	p.Arg782Leu	missense splice_region	Exon 17 of 17	ENSP00000334522.2	Q14114-4

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

African (AFR)

AF:

0.00

AC:

AN:

32586

American (AMR)

AF:

0.00

AC:

AN:

39690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25608

East Asian (EAS)

AF:

0.00

AC:

AN:

39312

South Asian (SAS)

AF:

0.00

AC:

AN:

82186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105160

Other (OTH)

AF:

0.00

AC:

AN:

59744

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

49998

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.50

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

0.69

PhyloP100

7.2

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.53

REVEL

Uncertain

0.63

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Polyphen

1.0

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

Mutation Taster

=32/68

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over