rs3820198

Variant names:

• chr1-53326979-A-C
• rs3820198
• NM_004631.5:c.138T>G

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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 the same amino acid substitution has been previously reported as Likely benign in 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
LRP8	NM_004631.5	c.138T>G	p.Asp46Glu	missense_variant	Exon 2 of 19	ENST00000306052.12	NP_004622.2
LRP8	NM_001018054.3	c.138T>G	p.Asp46Glu	missense_variant	Exon 2 of 18		NP_001018064.1
LRP8	NM_033300.4	c.138T>G	p.Asp46Glu	missense_variant	Exon 2 of 17		NP_150643.2
LRP8	NM_017522.5	c.138T>G	p.Asp46Glu	missense_variant	Exon 2 of 16		NP_059992.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12	c.138T>G	p.Asp46Glu	missense_variant	Exon 2 of 19	1	NM_004631.5	ENSP00000303634.6

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

GnomAD2 exomes AF: 0.396 AC: 99269 AN: 250518 AF XY: 0.395

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 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 AC: 28990 AN: 33468

Gnomad4 AMR exome AF: 0.253 AC: 11326 AN: 44714

Gnomad4 ASJ exome AF: 0.406 AC: 10611 AN: 26128

Gnomad4 EAS exome AF: 0.457 AC: 18145 AN: 39690

Gnomad4 SAS exome AF: 0.433 AC: 37318 AN: 86232

Gnomad4 FIN exome AF: 0.385 AC: 20292 AN: 52660

Gnomad4 NFE exome AF: 0.352 AC: 391234 AN: 1111864

Gnomad4 Remaining exome AF: 0.400 AC: 24125 AN: 60374

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 AC: 0.842095 AN: 0.842095

Gnomad4 AMR AF: 0.337 AC: 0.336735 AN: 0.336735

Gnomad4 ASJ AF: 0.395 AC: 0.395389 AN: 0.395389

Gnomad4 EAS AF: 0.443 AC: 0.443173 AN: 0.443173

Gnomad4 SAS AF: 0.426 AC: 0.42558 AN: 0.42558

Gnomad4 FIN AF: 0.392 AC: 0.391864 AN: 0.391864

Gnomad4 NFE AF: 0.356 AC: 0.356392 AN: 0.356392

Gnomad4 OTH AF: 0.448 AC: 0.447917 AN: 0.447917

Alfa AF: 0.409 Hom.: 44411

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
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
Mutation Taster		=92/8	polymorphism (auto)

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;