rs5174

chr1-53247055-C-Achr1-53247055-C-Gchr1-53247055-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_004631.5(LRP8):c.2855G>T(p.Arg952Leu) variant causes a missense, splice region change. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRP8 NM_004631.5 missense, splice_region
• Scores: Splicing: ADA: 0.9750
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP8	NM_004631.5	c.2855G>T	p.Arg952Leu	missense_variant, splice_region_variant	19/19	ENST00000306052.12
LRP8	NM_001018054.3	c.2678G>T	p.Arg893Leu	missense_variant, splice_region_variant	18/18
LRP8	NM_033300.4	c.2345G>T	p.Arg782Leu	missense_variant, splice_region_variant	17/17
LRP8	NM_017522.5	c.2066G>T	p.Arg689Leu	missense_variant, splice_region_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP8	ENST00000306052.12	c.2855G>T	p.Arg952Leu	missense_variant, splice_region_variant	19/19	1	NM_004631.5	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Benign	0.051	T;.;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T;.;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.50	T;D;D;D;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.69	N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.53	N;D;D;N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D;T;T;T;D
Sift4G	Pathogenic	0.0	D;T;T;T;D
Polyphen		1.0	D;B;P;D;D
Vest4		0.59
MutPred		0.27		Gain of sheet (P = 0.0344);.;.;.;.;
MVP		0.95
MPC		1.1
ClinPred		0.84	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.060		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: rs5174; hg19: chr1-53712727;