1-53250719-T-C

Variant names:

• chr1-53250719-T-C
• NM_004631.5:c.2647A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004631.5(LRP8):​c.2647A>G​(p.Thr883Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. T883P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRP8 NM_004631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.775

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]

LOC105378728 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12356207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP8	NM_004631.5	c.2647A>G	p.Thr883Ala	missense_variant	Exon 17 of 19	ENST00000306052.12	NP_004622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12	c.2647A>G	p.Thr883Ala	missense_variant	Exon 17 of 19	1	NM_004631.5	ENSP00000303634.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727218

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: 8.99e-7

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	0.085
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;.;.;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T;T;.;T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.69	N;N;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.077	T;T;D;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.0090	B;B;B;B;B
Vest4		0.13
MutPred		0.43		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;
MVP		0.68
MPC		0.38
ClinPred		0.11	T
GERP RS		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.32

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-53716391;