chr12-57166026-G-A

Variant names:

• chr12-57166026-G-A
• rs1800174
• NM_002332.3:c.2672-58G>A

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.2672-58G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,612,696 control chromosomes in the GnomAD database, including 88,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11051 hom., cov: 33)
  • Exomes 𝑓: 0.32 (77513 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.367
• Publications: 19 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=-0.89).
• BP6: Variant 12-57166026-G-A is Benign according to our data. Variant chr12-57166026-G-A is described in ClinVar as Benign. ClinVar VariationId is 1242385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.2672-58G>A		intron_variant	Intron 16 of 88	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.2672-58G>A		intron_variant	Intron 16 of 88	1	NM_002332.3	ENSP00000243077.3
LRP1	ENST00000556830.1	n.1519-58G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56570 AN: 152058 Hom.: 11037 Cov.: 33

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.363

GnomAD4 exome AF: 0.320 AC: 467486 AN: 1460518 Hom.: 77513 Cov.: 37 AF XY: 0.314 AC XY: 228286 AN XY: 726402

African (AFR) AF: 0.473 AC: 15834 AN: 33452

American (AMR) AF: 0.500 AC: 22329 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7825 AN: 26074

East Asian (EAS) AF: 0.360 AC: 14300 AN: 39674

South Asian (SAS) AF: 0.212 AC: 18255 AN: 86168

European-Finnish (FIN) AF: 0.400 AC: 21302 AN: 53282

Middle Eastern (MID) AF: 0.327 AC: 1882 AN: 5754

European-Non Finnish (NFE) AF: 0.312 AC: 346205 AN: 1111078

Other (OTH) AF: 0.324 AC: 19554 AN: 60352

GnomAD4 genome AF: 0.372 AC: 56618 AN: 152178 Hom.: 11051 Cov.: 33 AF XY: 0.371 AC XY: 27599 AN XY: 74406

African (AFR) AF: 0.474 AC: 19656 AN: 41494

American (AMR) AF: 0.392 AC: 5992 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1063 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2058 AN: 5170

South Asian (SAS) AF: 0.231 AC: 1117 AN: 4828

European-Finnish (FIN) AF: 0.395 AC: 4188 AN: 10608

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21299 AN: 68000

Other (OTH) AF: 0.359 AC: 758 AN: 2112

Alfa AF: 0.343 Hom.: 1497

Bravo AF: 0.387

Asia WGS AF: 0.370 AC: 1286 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.42
PhyloP100		-0.37
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: rs1800174; hg19: chr12-57559809; COSMIC: COSV107290354; COSMIC: COSV107290354;