12-57175646-A-G

Variant names:

• chr12-57175646-A-G
• rs483353013
• NM_002332.3:c.3734A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_002332.3(LRP1):​c.3734A>G​(p.Lys1245Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRP1 NM_002332.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-57175646-A-G is Pathogenic according to our data. Variant chr12-57175646-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 132834.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-57175646-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.3734A>G	p.Lys1245Arg	missense_variant	Exon 23 of 89	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.3734A>G	p.Lys1245Arg	missense_variant	Exon 23 of 89	1	NM_002332.3	ENSP00000243077.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244788 Hom.: 0 AF XY: 0.00000758 AC XY: 1 AN XY: 131934

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: 0.0000345

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453140 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 721718

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: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Keratosis pilaris Pathogenic:1

Mar 04, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Atrophoderma vermiculatum Other:1

-

Department of Immunology, Genetics and Pathology, Uppsala University

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.74	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.53
Sift	Benign	0.049	D
Sift4G	Benign	0.17	T
Polyphen		0.91	P
Vest4		0.71
MutPred		0.44		Loss of methylation at K1245 (P = 9e-04);
MVP		0.69
ClinPred		0.58	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs483353013; hg19: chr12-57569429;