rs1469864810

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002332.3(LRP1):​c.635C>A​(p.Thr212Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T212M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRP1
NM_002332.3 missense

Scores

6
8
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.05
Variant links:
Genes affected
LRP1 (HGNC:6692): (LDL receptor related protein 1) This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer's disease patients. [provided by RefSeq, Oct 2015]
LRP1-AS (HGNC:51694): (LRP1 antisense RNA)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRP1NM_002332.3 linkc.635C>A p.Thr212Lys missense_variant Exon 6 of 89 ENST00000243077.8 NP_002323.2 Q07954-1Q59FG2
LRP1-ASNR_131938.2 linkn.182-201G>T intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRP1ENST00000243077.8 linkc.635C>A p.Thr212Lys missense_variant Exon 6 of 89 1 NM_002332.3 ENSP00000243077.3 Q07954-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727236
show subpopulations
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:
0.00000180
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
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
.;T;.;T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Uncertain
0.64
D
MutationAssessor
Benign
1.8
.;L;L;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-1.9
N;N;N;N
REVEL
Pathogenic
0.70
Sift
Uncertain
0.024
D;T;D;T
Sift4G
Uncertain
0.032
D;D;T;T
Polyphen
1.0
D;D;.;D
Vest4
0.94
MutPred
0.59
Gain of catalytic residue at Q207 (P = 0.0184);Gain of catalytic residue at Q207 (P = 0.0184);Gain of catalytic residue at Q207 (P = 0.0184);Gain of catalytic residue at Q207 (P = 0.0184);
MVP
0.92
ClinPred
0.96
D
GERP RS
5.1
Varity_R
0.31
gMVP
0.88

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: chr12-57539067; API