1-53247055-C-G

Variant names:

• chr1-53247055-C-G
• rs5174
• NM_004631.5:c.2855G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004631.5(LRP8):​c.2855G>C​(p.Arg952Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP8 NM_004631.5 missense, splice_region
• Scores: Splicing: ADA: 0.9729
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18
• Publications: 82 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2855G>C	p.Arg952Pro	missense splice_region	Exon 19 of 19	NP_004622.2	Q14114-1
	LRP8	NM_001018054.3		c.2678G>C	p.Arg893Pro	missense splice_region	Exon 18 of 18	NP_001018064.1	Q14114-3
	LRP8	NM_033300.4		c.2345G>C	p.Arg782Pro	missense splice_region	Exon 17 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.2855G>C	p.Arg952Pro	missense splice_region	Exon 19 of 19	ENSP00000303634.6	Q14114-1
	LRP8	ENST00000371454.6	TSL:1	c.2678G>C	p.Arg893Pro	missense splice_region	Exon 18 of 18	ENSP00000360509.2	Q14114-3
	LRP8	ENST00000347547.7	TSL:1	c.2345G>C	p.Arg782Pro	missense splice_region	Exon 17 of 17	ENSP00000334522.2	Q14114-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 49998

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.69	N
PhyloP100		7.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.23		Gain of loop (P = 0.0166)
MVP		0.93
MPC		1.4
ClinPred		0.86	D
GERP RS		5.4
Varity_R		0.33
gMVP		0.26
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.85
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

Other links and lift over

dbSNP: rs5174; hg19: chr1-53712727;