chr12-57138565-C-A

Variant names:

• chr12-57138565-C-A
• rs144902096
• NM_002332.3:c.174C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• keratosis follicularis spinulosa decalvans

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrophoderma vermiculata

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• developmental dysplasia of the hip 3

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• keratosis pilaris atrophicans

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002332.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	NM_002332.3	MANE Select	c.174C>A	p.Asp58Glu	missense	Exon 2 of 89	NP_002323.2	Q07954-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	ENST00000243077.8	TSL:1 MANE Select	c.174C>A	p.Asp58Glu	missense	Exon 2 of 89	ENSP00000243077.3	Q07954-1
	LRP1	ENST00000554174.1	TSL:1	c.174C>A	p.Asp58Glu	missense	Exon 2 of 8	ENSP00000451737.1	Q6PJ72
	LRP1	ENST00000553277.5	TSL:1	c.174C>A	p.Asp58Glu	missense	Exon 2 of 7	ENSP00000451449.1	Q7Z7K9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251274 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	6.5
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.44	N
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		-1.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.70		Gain of catalytic residue at G56 (P = 0.148)
MVP		0.93
ClinPred		0.98	D
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.58
gMVP		0.96
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs144902096; hg19: chr12-57532348;