12-57197443-T-C

Variant names:

• chr12-57197443-T-C
• rs1800165
• NM_002332.3:c.9162+59T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002332.3(LRP1):​c.9162+59T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,609,872 control chromosomes in the GnomAD database, including 97,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14926 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82644 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.75
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-57197443-T-C is Benign according to our data. Variant chr12-57197443-T-C is described in ClinVar as Benign. ClinVar VariationId is 1267665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 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.9162+59T>C		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.9162+59T>C		intron	N/A	ENSP00000243077.3

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63714 AN: 151812 Hom.: 14889 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.394

GnomAD4 exome AF: 0.328 AC: 477813 AN: 1457942 Hom.: 82644 Cov.: 32 AF XY: 0.321 AC XY: 233063 AN XY: 725336

African (AFR) AF: 0.637 AC: 21251 AN: 33340

American (AMR) AF: 0.512 AC: 22754 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 8215 AN: 26018

East Asian (EAS) AF: 0.409 AC: 16240 AN: 39666

South Asian (SAS) AF: 0.213 AC: 18352 AN: 86138

European-Finnish (FIN) AF: 0.399 AC: 21301 AN: 53336

Middle Eastern (MID) AF: 0.335 AC: 1919 AN: 5730

European-Non Finnish (NFE) AF: 0.313 AC: 347290 AN: 1109068

Other (OTH) AF: 0.340 AC: 20491 AN: 60228

GnomAD4 genome AF: 0.420 AC: 63805 AN: 151930 Hom.: 14926 Cov.: 32 AF XY: 0.418 AC XY: 31002 AN XY: 74238

African (AFR) AF: 0.629 AC: 26075 AN: 41430

American (AMR) AF: 0.409 AC: 6253 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1118 AN: 3472

East Asian (EAS) AF: 0.458 AC: 2353 AN: 5142

South Asian (SAS) AF: 0.233 AC: 1121 AN: 4810

European-Finnish (FIN) AF: 0.393 AC: 4151 AN: 10558

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21420 AN: 67932

Other (OTH) AF: 0.393 AC: 825 AN: 2100

Alfa AF: 0.266 Hom.: 928

Bravo AF: 0.441

Asia WGS AF: 0.419 AC: 1457 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.2
DANN	Benign	0.16
PhyloP100		-3.8
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: rs1800165; hg19: chr12-57591226; COSMIC: COSV54505417; COSMIC: COSV54505417;