1-53272511-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004631.5(LRP8):​c.1007-1165T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000983 in 1,017,484 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: LRP8 NM_004631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP8	NM_004631.5	c.1007-1165T>A		intron_variant	Intron 6 of 18	ENST00000306052.12	NP_004622.2
LRP8	NM_001018054.3	c.1007-1165T>A		intron_variant	Intron 6 of 17		NP_001018064.1
LRP8	NM_033300.4	c.497-1165T>A		intron_variant	Intron 4 of 16		NP_150643.2
LRP8	NM_017522.5	c.620-1165T>A		intron_variant	Intron 5 of 15		NP_059992.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12	c.1007-1165T>A		intron_variant	Intron 6 of 18	1	NM_004631.5	ENSP00000303634.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.83e-7 AC: 1 AN: 1017484 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 504014

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22016

American (AMR) AF: 0.00 AC: 0 AN: 27690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14606

East Asian (EAS) AF: 0.00 AC: 0 AN: 12806

South Asian (SAS) AF: 0.00 AC: 0 AN: 72390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4148

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 813120

Other (OTH) AF: 0.00 AC: 0 AN: 37678

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.36
DANN	Benign	0.65
PhyloP100		-0.16

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;