NM_002332.3:c.190+1326C>A

Variant names:

• chr12-57139907-C-A
• rs4759277
• NM_002332.3:c.190+1326C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002332.3(LRP1):​c.190+1326C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 152,010 control chromosomes in the GnomAD database, including 11,172 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (11172 hom., cov: 32)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 39 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

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.190+1326C>A		intron	N/A	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.190+1326C>A		intron	N/A	ENSP00000243077.3	Q07954-1
	LRP1	ENST00000554174.1	TSL:1	c.190+1326C>A		intron	N/A	ENSP00000451737.1	Q6PJ72
	LRP1	ENST00000553277.5	TSL:1	c.190+1326C>A		intron	N/A	ENSP00000451449.1	Q7Z7K9

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57377 AN: 151892 Hom.: 11152 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.342

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.378 AC: 57443 AN: 152010 Hom.: 11172 Cov.: 32 AF XY: 0.378 AC XY: 28084 AN XY: 74292

African (AFR) AF: 0.431 AC: 17849 AN: 41434

American (AMR) AF: 0.472 AC: 7207 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3470

East Asian (EAS) AF: 0.244 AC: 1263 AN: 5168

South Asian (SAS) AF: 0.344 AC: 1655 AN: 4810

European-Finnish (FIN) AF: 0.345 AC: 3648 AN: 10566

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23774 AN: 67970

Other (OTH) AF: 0.340 AC: 719 AN: 2112

Alfa AF: 0.355 Hom.: 15225

Bravo AF: 0.388

Asia WGS AF: 0.341 AC: 1187 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.082
DANN	Benign	0.61
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
Mutation Taster		=98/2	polymorphism (auto)

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: rs4759277; hg19: chr12-57533690; COSMIC: COSV54525184; COSMIC: COSV54525184;