rs5173

Variant names:

• chr1-53250819-T-C
• rs5173
• NM_004631.5:c.2547A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004631.5(LRP8):​c.2547A>G​(p.Arg849Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,614,060 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (22 hom., cov: 30)
  • Exomes 𝑓: 0.00087 (13 hom.)
• Consequence: LRP8 NM_004631.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.212
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-53250819-T-C is Benign according to our data. Variant chr1-53250819-T-C is described in ClinVar as Benign. ClinVar VariationId is 714069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.212 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00885 (1347/152174) while in subpopulation AFR AF = 0.0309 (1284/41500). AF 95% confidence interval is 0.0295. There are 22 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	NM_004631.5	MANE Select	c.2547A>G	p.Arg849Arg	synonymous	Exon 17 of 19	NP_004622.2	Q14114-1
	LRP8	NM_001018054.3		c.2547A>G	p.Arg849Arg	synonymous	Exon 17 of 18	NP_001018064.1	Q14114-3
	LRP8	NM_033300.4		c.2037A>G	p.Arg679Arg	synonymous	Exon 15 of 17	NP_150643.2	Q14114-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	ENST00000306052.12	TSL:1 MANE Select	c.2547A>G	p.Arg849Arg	synonymous	Exon 17 of 19	ENSP00000303634.6	Q14114-1
	LRP8	ENST00000371454.6	TSL:1	c.2547A>G	p.Arg849Arg	synonymous	Exon 17 of 18	ENSP00000360509.2	Q14114-3
	LRP8	ENST00000347547.7	TSL:1	c.2037A>G	p.Arg679Arg	synonymous	Exon 15 of 17	ENSP00000334522.2	Q14114-4

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1338 AN: 152056 Hom.: 21 Cov.: 30

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00244 AC: 613 AN: 251426 AF XY: 0.00177

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000867 AC: 1268 AN: 1461886 Hom.: 13 Cov.: 32 AF XY: 0.000754 AC XY: 548 AN XY: 727246

African (AFR) AF: 0.0301 AC: 1009 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1112006

Other (OTH) AF: 0.00204 AC: 123 AN: 60396

GnomAD4 genome AF: 0.00885 AC: 1347 AN: 152174 Hom.: 22 Cov.: 30 AF XY: 0.00829 AC XY: 617 AN XY: 74394

African (AFR) AF: 0.0309 AC: 1284 AN: 41500

American (AMR) AF: 0.00281 AC: 43 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68004

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00378 Hom.: 13

Bravo AF: 0.0103

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.7
DANN	Benign	0.63
PhyloP100		-0.21
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs5173; hg19: chr1-53716491;