12-57139199-T-C

Variant names:

• chr12-57139199-T-C
• rs715948
• NM_002332.3:c.190+618T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002332.3(LRP1):​c.190+618T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 151,976 control chromosomes in the GnomAD database, including 39,005 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (39005 hom., cov: 31)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.413
• Publications: 34 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.190+618T>C		intron_variant	Intron 2 of 88	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.190+618T>C		intron_variant	Intron 2 of 88	1	NM_002332.3	ENSP00000243077.3
LRP1	ENST00000554174.1	c.190+618T>C		intron_variant	Intron 2 of 7	1		ENSP00000451737.1
LRP1	ENST00000553277.5	c.190+618T>C		intron_variant	Intron 2 of 6	1		ENSP00000451449.1
LRP1	ENST00000338962.8	c.190+618T>C		intron_variant	Intron 2 of 6	1		ENSP00000341264.4

Frequencies

GnomAD3 genomes AF: 0.713 AC: 108291 AN: 151858 Hom.: 38962 Cov.: 31

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.690

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.713 AC: 108389 AN: 151976 Hom.: 39005 Cov.: 31 AF XY: 0.711 AC XY: 52801 AN XY: 74300

African (AFR) AF: 0.795 AC: 32935 AN: 41410

American (AMR) AF: 0.721 AC: 11027 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2637 AN: 3470

East Asian (EAS) AF: 0.488 AC: 2511 AN: 5150

South Asian (SAS) AF: 0.668 AC: 3216 AN: 4814

European-Finnish (FIN) AF: 0.670 AC: 7085 AN: 10580

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.690 AC: 46863 AN: 67942

Other (OTH) AF: 0.686 AC: 1446 AN: 2108

Alfa AF: 0.696 Hom.: 83116

Bravo AF: 0.718

Asia WGS AF: 0.652 AC: 2269 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.7
DANN	Benign	0.47
PhyloP100		0.41
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: rs715948; hg19: chr12-57532982;