chr12-57167668-C-T

Variant names:

• chr12-57167668-C-T
• rs1800176
• NM_002332.3:c.2995+144C>T

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.2995+144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 659,218 control chromosomes in the GnomAD database, including 47,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (17325 hom., cov: 33)
  • Exomes 𝑓: 0.33 (30569 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.81
• Publications: 12 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=-0.85).
• BP6: Variant 12-57167668-C-T is Benign according to our data. Variant chr12-57167668-C-T is described in ClinVar as Benign. ClinVar VariationId is 1269528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.2995+144C>T		intron_variant	Intron 19 of 88	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.2995+144C>T		intron_variant	Intron 19 of 88	1	NM_002332.3	ENSP00000243077.3
LRP1	ENST00000553446.1	n.80+144C>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67300 AN: 151916 Hom.: 17287 Cov.: 33

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.408

GnomAD4 exome AF: 0.333 AC: 169038 AN: 507184 Hom.: 30569 AF XY: 0.323 AC XY: 87161 AN XY: 269602

African (AFR) AF: 0.709 AC: 9923 AN: 13996

American (AMR) AF: 0.486 AC: 11695 AN: 24050

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 4633 AN: 14910

East Asian (EAS) AF: 0.398 AC: 12426 AN: 31194

South Asian (SAS) AF: 0.214 AC: 10830 AN: 50632

European-Finnish (FIN) AF: 0.398 AC: 12646 AN: 31804

Middle Eastern (MID) AF: 0.328 AC: 956 AN: 2916

European-Non Finnish (NFE) AF: 0.310 AC: 95904 AN: 309638

Other (OTH) AF: 0.357 AC: 10025 AN: 28044

GnomAD4 genome AF: 0.443 AC: 67391 AN: 152034 Hom.: 17325 Cov.: 33 AF XY: 0.440 AC XY: 32718 AN XY: 74312

African (AFR) AF: 0.713 AC: 29554 AN: 41444

American (AMR) AF: 0.419 AC: 6407 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1103 AN: 3470

East Asian (EAS) AF: 0.452 AC: 2330 AN: 5156

South Asian (SAS) AF: 0.231 AC: 1116 AN: 4826

European-Finnish (FIN) AF: 0.394 AC: 4169 AN: 10580

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21368 AN: 67964

Other (OTH) AF: 0.406 AC: 858 AN: 2112

Alfa AF: 0.380 Hom.: 3158

Bravo AF: 0.468

Asia WGS AF: 0.426 AC: 1478 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.48
DANN	Benign	0.62
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1800176; hg19: chr12-57561451; COSMIC: COSV54517285; COSMIC: COSV54517285;