chr1-53250819-T-C

Position:

• chr1-53250819-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004631.5(LRP8):​c.2547A>G​(p.Arg849=) 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

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1347 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP8	NM_004631.5	c.2547A>G	p.Arg849=	synonymous_variant	17/19	ENST00000306052.12	NP_004622.2
LRP8	NM_001018054.3	c.2547A>G	p.Arg849=	synonymous_variant	17/18		NP_001018064.1
LRP8	NM_033300.4	c.2037A>G	p.Arg679=	synonymous_variant	15/17		NP_150643.2
LRP8	NM_017522.5	c.1935A>G	p.Arg645=	synonymous_variant	15/16		NP_059992.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12	c.2547A>G	p.Arg849=	synonymous_variant	17/19	1	NM_004631.5	ENSP00000303634	A2

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

GnomAD3 exomes AF: 0.00244 AC: 613 AN: 251426 Hom.: 14 AF XY: 0.00177 AC XY: 241 AN XY: 135894

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 SAS exome AF: 0.000131

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

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00204

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

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00279 Hom.: 8

Bravo AF: 0.0103

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.7
DANN	Benign	0.63

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: rs5173; hg19: chr1-53716491;