rs1800154

chr12-57195876-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002332.3(LRP1):c.8574C>T(p.Cys2858=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,318 control chromosomes in the GnomAD database, including 90,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11613 hom., cov: 33)
  • Exomes 𝑓: 0.32 (78705 hom.)
• Consequence: LRP1 NM_002332.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.69

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-57195876-C-T is Benign according to our data. Variant chr12-57195876-C-T is described in ClinVar as [Benign]. Clinvar id is 1222429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3	c.8574C>T	p.Cys2858=	synonymous_variant	54/89	ENST00000243077.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8	c.8574C>T	p.Cys2858=	synonymous_variant	54/89	1	NM_002332.3	P1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57754 AN: 151914 Hom.: 11596 Cov.: 33

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.368

GnomAD3 exomes AF: 0.357 AC: 89396 AN: 250394 Hom.: 17262 AF XY: 0.338 AC XY: 45782 AN XY: 135402

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.397

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.318

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.322 AC: 470705 AN: 1461288 Hom.: 78705 Cov.: 58 AF XY: 0.316 AC XY: 229859 AN XY: 726976

Gnomad4 AFR exome AF: 0.498

Gnomad4 AMR exome AF: 0.503

Gnomad4 ASJ exome AF: 0.304

Gnomad4 EAS exome AF: 0.368

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.400

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.380 AC: 57808 AN: 152030 Hom.: 11613 Cov.: 33 AF XY: 0.379 AC XY: 28133 AN XY: 74310

Gnomad4 AFR AF: 0.499

Gnomad4 AMR AF: 0.397

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.365

Alfa AF: 0.338 Hom.: 4618

Bravo AF: 0.397

Asia WGS AF: 0.374 AC: 1301 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.308

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Keratosis pilaris Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

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	-0.31
Cadd	Benign	2.2
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800154; hg19: chr12-57589659; COSMIC: COSV54503099; COSMIC: COSV54503099;