1-53266643-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004631.5(LRP8):c.1257C>A(p.Gly419=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,612,990 control chromosomes in the GnomAD database, including 131,104 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10586 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120518 hom.)
• Consequence: LRP8 NM_004631.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.876

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]

LOC105378728 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=0.876 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP8	NM_004631.5	c.1257C>A	p.Gly419=	synonymous_variant	9/19	ENST00000306052.12
LOC105378728	XR_947355.3	n.4612-453G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP8	ENST00000306052.12	c.1257C>A	p.Gly419=	synonymous_variant	9/19	1	NM_004631.5	A2

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54273 AN: 151848 Hom.: 10584 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.319

GnomAD3 exomes AF: 0.382 AC: 96107 AN: 251266 Hom.: 20067 AF XY: 0.374 AC XY: 50727 AN XY: 135796

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.643

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.398 AC: 581475 AN: 1461024 Hom.: 120518 Cov.: 38 AF XY: 0.392 AC XY: 285127 AN XY: 726852

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.363

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.645

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.440

Gnomad4 NFE exome AF: 0.413

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.357 AC: 54298 AN: 151966 Hom.: 10586 Cov.: 32 AF XY: 0.356 AC XY: 26476 AN XY: 74294

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.629

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.414

Gnomad4 OTH AF: 0.323

Alfa AF: 0.385 Hom.: 19537

Bravo AF: 0.350

Asia WGS AF: 0.380 AC: 1321 AN: 3478

EpiCase AF: 0.388

EpiControl AF: 0.387

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	9.5
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2297660; hg19: chr1-53732315; COSMIC: COSV60096180; COSMIC: COSV60096180;