chr1-53250744-G-A

Variant names:

• chr1-53250744-G-A
• rs3737983
• NM_004631.5:c.2622C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004631.5(LRP8):​c.2622C>T​(p.Asp874Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,612,428 control chromosomes in the GnomAD database, including 141,610 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 0.38 (11875 hom., cov: 31)
  • Exomes 𝑓: 0.41 (129735 hom.)
• Consequence: LRP8 NM_004631.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.466
• Publications: 40 publications found

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)

LOC105378728 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP7: Synonymous conserved (PhyloP=-0.466 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	NM_004631.5	MANE Select	c.2622C>T	p.Asp874Asp	synonymous	Exon 17 of 19	NP_004622.2
	LRP8	NM_001018054.3		c.2622C>T	p.Asp874Asp	synonymous	Exon 17 of 18	NP_001018064.1
	LRP8	NM_033300.4		c.2112C>T	p.Asp704Asp	synonymous	Exon 15 of 17	NP_150643.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	ENST00000306052.12	TSL:1 MANE Select	c.2622C>T	p.Asp874Asp	synonymous	Exon 17 of 19	ENSP00000303634.6
	LRP8	ENST00000371454.6	TSL:1	c.2622C>T	p.Asp874Asp	synonymous	Exon 17 of 18	ENSP00000360509.2
	LRP8	ENST00000347547.7	TSL:1	c.2112C>T	p.Asp704Asp	synonymous	Exon 15 of 17	ENSP00000334522.2

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57907 AN: 151788 Hom.: 11868 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.341

GnomAD2 exomes AF: 0.403 AC: 101426 AN: 251392 AF XY: 0.395

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.723

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.413 AC: 603481 AN: 1460522 Hom.: 129735 Cov.: 37 AF XY: 0.408 AC XY: 296541 AN XY: 726648

African (AFR) AF: 0.267 AC: 8932 AN: 33462

American (AMR) AF: 0.368 AC: 16453 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8759 AN: 26136

East Asian (EAS) AF: 0.720 AC: 28595 AN: 39696

South Asian (SAS) AF: 0.236 AC: 20354 AN: 86246

European-Finnish (FIN) AF: 0.462 AC: 24691 AN: 53388

Middle Eastern (MID) AF: 0.259 AC: 1495 AN: 5768

European-Non Finnish (NFE) AF: 0.424 AC: 470436 AN: 1110744

Other (OTH) AF: 0.394 AC: 23766 AN: 60360

GnomAD4 genome AF: 0.381 AC: 57947 AN: 151906 Hom.: 11875 Cov.: 31 AF XY: 0.381 AC XY: 28293 AN XY: 74244

African (AFR) AF: 0.272 AC: 11261 AN: 41448

American (AMR) AF: 0.370 AC: 5649 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1154 AN: 3472

East Asian (EAS) AF: 0.705 AC: 3632 AN: 5152

South Asian (SAS) AF: 0.248 AC: 1192 AN: 4812

European-Finnish (FIN) AF: 0.467 AC: 4920 AN: 10540

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28889 AN: 67906

Other (OTH) AF: 0.346 AC: 730 AN: 2112

Alfa AF: 0.410 Hom.: 65747

Bravo AF: 0.373

EpiCase AF: 0.400

EpiControl AF: 0.395

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.4
DANN	Benign	0.50
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3737983; hg19: chr1-53716416; COSMIC: COSV60098479; COSMIC: COSV60098479;