rs3820198

chr1-53326979-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004631.5(LRP8):c.138T>G(p.Asp46Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,613,024 control chromosomes in the GnomAD database, including 129,517 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (22436 hom., cov: 33)
  • Exomes 𝑓: 0.37 (107081 hom.)
• Consequence: LRP8 NM_004631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.363

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.066132E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP8	NM_004631.5	c.138T>G	p.Asp46Glu	missense_variant	2/19	ENST00000306052.12
LRP8	NM_001018054.3	c.138T>G	p.Asp46Glu	missense_variant	2/18
LRP8	NM_033300.4	c.138T>G	p.Asp46Glu	missense_variant	2/17
LRP8	NM_017522.5	c.138T>G	p.Asp46Glu	missense_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP8	ENST00000306052.12	c.138T>G	p.Asp46Glu	missense_variant	2/19	1	NM_004631.5	A2

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75507 AN: 152008 Hom.: 22380 Cov.: 33

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.452

GnomAD3 exomes AF: 0.396 AC: 99269 AN: 250518 Hom.: 22064 AF XY: 0.395 AC XY: 53506 AN XY: 135550

Gnomad AFR exome AF: 0.853

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.445

Gnomad SAS exome AF: 0.434

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.361

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.373 AC: 544810 AN: 1460898 Hom.: 107081 Cov.: 48 AF XY: 0.374 AC XY: 272137 AN XY: 726826

Gnomad4 AFR exome AF: 0.866

Gnomad4 AMR exome AF: 0.253

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.457

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.385

Gnomad4 NFE exome AF: 0.352

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.497 AC: 75611 AN: 152126 Hom.: 22436 Cov.: 33 AF XY: 0.495 AC XY: 36811 AN XY: 74366

Gnomad4 AFR AF: 0.842

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.395

Gnomad4 EAS AF: 0.443

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.448

Alfa AF: 0.387 Hom.: 24957

Bravo AF: 0.507

TwinsUK AF: 0.349 AC: 1293

ALSPAC AF: 0.353 AC: 1359

ESP6500AA AF: 0.825 AC: 3635

ESP6500EA AF: 0.360 AC: 3093

ExAC AF: 0.411 AC: 49900

Asia WGS AF: 0.508 AC: 1771 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	10
Dann	Benign	0.62
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.022	T;T;T;T
MetaRNN	Benign	0.0000021	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.10	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.71	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.021
MutPred		0.23		Gain of methylation at K49 (P = 0.0895);Gain of methylation at K49 (P = 0.0895);Gain of methylation at K49 (P = 0.0895);Gain of methylation at K49 (P = 0.0895);
MPC		0.95
ClinPred		0.00023	T
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs3820198; hg19: chr1-53792651; COSMIC: COSV60095959; COSMIC: COSV60095959;