Variant 12-57143756-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_002332.3(LRP1):c.406A>C(p.Asn136His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

LRP1
NM_002332.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08

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.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity LRP1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP1. . Gene score misZ 8.2463 (greater than the threshold 3.09). Trascript score misZ 12.011 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia, atrophoderma vermiculata, keratosis pilaris atrophicans, keratosis follicularis spinulosa decalvans.

BP4

Computational evidence support a benign effect (MetaRNN=0.27520633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3 linkuse as main transcript	c.406A>C	p.Asn136His	missense_variant	4/89	ENST00000243077.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8 linkuse as main transcript	c.406A>C	p.Asn136His	missense_variant	4/89	1	NM_002332.3	P1	Q07954-1
LRP1	ENST00000554174.1 linkuse as main transcript	c.406A>C	p.Asn136His	missense_variant	4/8	1
LRP1	ENST00000553277.5 linkuse as main transcript	c.406A>C	p.Asn136His	missense_variant	4/7	1
LRP1	ENST00000338962.8 linkuse as main transcript	c.406A>C	p.Asn136His	missense_variant	4/7	1			Q07954-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250970

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2024

The c.406A>C (p.N136H) alteration is located in exon 4 (coding exon 4) of the LRP1 gene. This alteration results from a A to C substitution at nucleotide position 406, causing the asparagine (N) at amino acid position 136 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T;.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

D;T;D;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.1

.;L;L;.

MutationTaster

Benign

0.62

D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.23

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.10

T;T;T;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.98

D;P;.;P

Vest4

0.38

MutPred

0.49

Gain of catalytic residue at S137 (P = 0);Gain of catalytic residue at S137 (P = 0);Gain of catalytic residue at S137 (P = 0);Gain of catalytic residue at S137 (P = 0);

MVP

0.61

ClinPred

0.74

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.64

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over