rs10876967

Variant names:

• chr12-57176810-G-A
• rs10876967
• NM_002332.3:c.3992-231G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-57176810-G-A
• chr12-57176810-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002332.3(LRP1):​c.3992-231G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 151,514 control chromosomes in the GnomAD database, including 10,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.37 (10834 hom., cov: 30)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.915
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-57176810-G-A is Benign according to our data. Variant chr12-57176810-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227748.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	NM_002332.3	MANE Select	c.3992-231G>A		intron	N/A	NP_002323.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	ENST00000243077.8	TSL:1 MANE Select	c.3992-231G>A		intron	N/A	ENSP00000243077.3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55788 AN: 151396 Hom.: 10819 Cov.: 30

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.369 AC: 55837 AN: 151514 Hom.: 10834 Cov.: 30 AF XY: 0.367 AC XY: 27187 AN XY: 73980

African (AFR) AF: 0.474 AC: 19530 AN: 41210

American (AMR) AF: 0.388 AC: 5919 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1072 AN: 3468

East Asian (EAS) AF: 0.403 AC: 2070 AN: 5134

South Asian (SAS) AF: 0.218 AC: 1043 AN: 4792

European-Finnish (FIN) AF: 0.396 AC: 4136 AN: 10454

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20830 AN: 67894

Other (OTH) AF: 0.356 AC: 749 AN: 2104

Alfa AF: 0.191 Hom.: 385

Bravo AF: 0.384

Asia WGS AF: 0.370 AC: 1285 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.39
PhyloP100		-0.92
Mutation Taster		=100/0	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: rs10876967; hg19: chr12-57570593; COSMIC: COSV54524291;