12-57141483-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.300C>T(p.Asp100=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,992 control chromosomes in the GnomAD database, including 17,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1265 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15953 hom.)
• Consequence: LRP1 NM_002332.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: -2.02

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=-0.35).
• BP6: Variant 12-57141483-C-T is Benign according to our data. Variant chr12-57141483-C-T is described in ClinVar as [Benign]. Clinvar id is 930178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57141483-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3	c.300C>T	p.Asp100=	synonymous_variant	3/89	ENST00000243077.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8	c.300C>T	p.Asp100=	synonymous_variant	3/89	1	NM_002332.3	P1
LRP1	ENST00000554174.1	c.300C>T	p.Asp100=	synonymous_variant	3/8	1
LRP1	ENST00000553277.5	c.300C>T	p.Asp100=	synonymous_variant	3/7	1
LRP1	ENST00000338962.8	c.300C>T	p.Asp100=	synonymous_variant	3/7	1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18129 AN: 152128 Hom.: 1262 Cov.: 32

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0668

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.129 AC: 32334 AN: 251146 Hom.: 2503 AF XY: 0.134 AC XY: 18155 AN XY: 135744

Gnomad AFR exome AF: 0.0525

Gnomad AMR exome AF: 0.0653

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.0555

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.144 AC: 210412 AN: 1461746 Hom.: 15953 Cov.: 32 AF XY: 0.145 AC XY: 105732 AN XY: 727182

Gnomad4 AFR exome AF: 0.0531

Gnomad4 AMR exome AF: 0.0677

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.0821

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.119 AC: 18129 AN: 152246 Hom.: 1265 Cov.: 32 AF XY: 0.123 AC XY: 9132 AN XY: 74436

Gnomad4 AFR AF: 0.0592

Gnomad4 AMR AF: 0.0865

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.0670

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.131

Alfa AF: 0.143 Hom.: 2677

Bravo AF: 0.107

Asia WGS AF: 0.0970 AC: 337 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.153

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Keratosis pilaris Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Endocrine Laboratory of Southeast University, Southeast University

Jan 01, 2019

early diagnosis and prevention on AD -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 22819221, 12732394, 28924541, 11076057, 9633759) -

LRP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	4.1
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1799986; hg19: chr12-57535266; COSMIC: COSV54511396; COSMIC: COSV54511396;