dbSNP rs144902096: LRP1:p.Asp58Glu (chr12-57138565-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

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

The NM_002332.3(LRP1):c.174C>A(p.Asp58Glu) 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 1,461,734 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. Synonymous variant affecting the same amino acid position (i.e. D58D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRP1
NM_002332.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.54

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 links:

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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, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3 link	c.174C>A	p.Asp58Glu	missense_variant	Exon 2 of 89	ENST00000243077.8	NP_002323.2	Q07954-1Q59FG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP1	ENST00000243077.8 link	c.174C>A	p.Asp58Glu	missense_variant	Exon 2 of 89	1	NM_002332.3	ENSP00000243077.3	Q07954-1
LRP1	ENST00000554174.1 link	c.174C>A	p.Asp58Glu	missense_variant	Exon 2 of 8	1		ENSP00000451737.1	Q6PJ72
LRP1	ENST00000553277.5 link	c.174C>A	p.Asp58Glu	missense_variant	Exon 2 of 7	1		ENSP00000451449.1	Q7Z7K9
LRP1	ENST00000338962.8 link	c.174C>A	p.Asp58Glu	missense_variant	Exon 2 of 7	1		ENSP00000341264.4	Q07954-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251274

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727186

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

6.5

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

.;D;.;D

Eigen

Benign

-0.024

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.44

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;H;H;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Uncertain

0.039

D;D;T;D

Polyphen

1.0

D;D;.;D

Vest4

0.84

MutPred

0.70

Gain of catalytic residue at G56 (P = 0.148);Gain of catalytic residue at G56 (P = 0.148);Gain of catalytic residue at G56 (P = 0.148);Gain of catalytic residue at G56 (P = 0.148);

MVP

0.93

ClinPred

0.98

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.58

gMVP

0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over