chr1-53250744-G-C

Variant names:

• chr1-53250744-G-C
• rs3737983
• NM_004631.5:c.2622C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004631.5(LRP8):​c.2622C>G​(p.Asp874Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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: 31)
• Consequence: LRP8 NM_004631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.466
• 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)

LOC105378728 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12812346).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	NM_004631.5	MANE Select	c.2622C>G	p.Asp874Glu	missense	Exon 17 of 19	NP_004622.2
	LRP8	NM_001018054.3		c.2622C>G	p.Asp874Glu	missense	Exon 17 of 18	NP_001018064.1
	LRP8	NM_033300.4		c.2112C>G	p.Asp704Glu	missense	Exon 15 of 17	NP_150643.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP8	ENST00000306052.12	TSL:1 MANE Select	c.2622C>G	p.Asp874Glu	missense	Exon 17 of 19	ENSP00000303634.6
	LRP8	ENST00000371454.6	TSL:1	c.2622C>G	p.Asp874Glu	missense	Exon 17 of 18	ENSP00000360509.2
	LRP8	ENST00000347547.7	TSL:1	c.2112C>G	p.Asp704Glu	missense	Exon 15 of 17	ENSP00000334522.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.47
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.044
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Polyphen		0.011	B
Vest4		0.16
MutPred		0.23		Gain of sheet (P = 0.1208)
MVP		0.68
MPC		0.37
ClinPred		0.040	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.027
gMVP		0.29
Mutation Taster		=77/23	polymorphism

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: rs3737983; hg19: chr1-53716416;