rs10876967

chr12-57176810-G-Achr12-57176810-G-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3	c.3992-231G>A		intron_variant		ENST00000243077.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8	c.3992-231G>A		intron_variant		1	NM_002332.3	P1

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

Gnomad4 AFR AF: 0.474

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.403

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.356

Alfa AF: 0.172 Hom.: 296

Bravo AF: 0.384

Asia WGS AF: 0.370 AC: 1285 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	3.2
Dann	Benign	0.39

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

Other links and lift over

dbSNP: rs10876967; hg19: chr12-57570593; COSMIC: COSV54524291;