NM_004631.5:c.1007-1165T>C

Variant names:

• chr1-53272511-A-G
• rs7546246
• NM_004631.5:c.1007-1165T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004631.5(LRP8):​c.1007-1165T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,166,998 control chromosomes in the GnomAD database, including 100,279 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 0.39 (12532 hom., cov: 33)
  • Exomes 𝑓: 0.41 (87747 hom.)
• Consequence: LRP8 NM_004631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158
• Publications: 7 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	NM_004631.5	MANE Select	c.1007-1165T>C		intron	N/A	NP_004622.2	Q14114-1
	LRP8	NM_001018054.3		c.1007-1165T>C		intron	N/A	NP_001018064.1	Q14114-3
	LRP8	NM_033300.4		c.497-1165T>C		intron	N/A	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.1007-1165T>C		intron	N/A	ENSP00000303634.6	Q14114-1
	LRP8	ENST00000371454.6	TSL:1	c.1007-1165T>C		intron	N/A	ENSP00000360509.2	Q14114-3
	LRP8	ENST00000347547.7	TSL:1	c.497-1165T>C		intron	N/A	ENSP00000334522.2	Q14114-4

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59656 AN: 152034 Hom.: 12526 Cov.: 33

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.351

GnomAD4 exome AF: 0.408 AC: 414446 AN: 1014844 Hom.: 87747 AF XY: 0.403 AC XY: 202485 AN XY: 502800

African (AFR) AF: 0.291 AC: 6410 AN: 21990

American (AMR) AF: 0.376 AC: 10381 AN: 27640

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 4870 AN: 14582

East Asian (EAS) AF: 0.777 AC: 9934 AN: 12786

South Asian (SAS) AF: 0.239 AC: 17311 AN: 72314

European-Finnish (FIN) AF: 0.454 AC: 5902 AN: 13004

Middle Eastern (MID) AF: 0.253 AC: 1047 AN: 4138

European-Non Finnish (NFE) AF: 0.424 AC: 343568 AN: 810798

Other (OTH) AF: 0.400 AC: 15023 AN: 37592

GnomAD4 genome AF: 0.392 AC: 59699 AN: 152154 Hom.: 12532 Cov.: 33 AF XY: 0.392 AC XY: 29119 AN XY: 74376

African (AFR) AF: 0.302 AC: 12555 AN: 41526

American (AMR) AF: 0.373 AC: 5706 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1162 AN: 3468

East Asian (EAS) AF: 0.762 AC: 3934 AN: 5162

South Asian (SAS) AF: 0.250 AC: 1206 AN: 4824

European-Finnish (FIN) AF: 0.463 AC: 4905 AN: 10594

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

European-Non Finnish (NFE) AF: 0.426 AC: 28954 AN: 67968

Other (OTH) AF: 0.356 AC: 751 AN: 2112

Alfa AF: 0.397 Hom.: 4726

Bravo AF: 0.385

Asia WGS AF: 0.471 AC: 1635 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.48
DANN	Benign	0.65
PhyloP100		-0.16
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs7546246; hg19: chr1-53738183;