12-57149789-C-T

Variant names:

• chr12-57149789-C-T
• rs10876966
• ENST00000553277.5:c.*60C>T

Variant summary

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

The ENST00000553277.5(LRP1):​c.*60C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 704,768 control chromosomes in the GnomAD database, including 16,787 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 0.19 (3004 hom., cov: 31)
  • Exomes 𝑓: 0.22 (13783 hom.)
• Consequence: LRP1 ENST00000553277.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 16 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.841+4299C>T		intron_variant	Intron 6 of 88	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000553277.5	c.*60C>T		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000451449.1
LRP1	ENST00000338962.8	c.*771C>T		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000341264.4
LRP1	ENST00000243077.8	c.841+4299C>T		intron_variant	Intron 6 of 88	1	NM_002332.3	ENSP00000243077.3
LRP1	ENST00000554174.1	c.841+4299C>T		intron_variant	Intron 6 of 7	1		ENSP00000451737.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28390 AN: 151978 Hom.: 3003 Cov.: 31

Gnomad AFR AF: 0.0883

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.197

GnomAD4 exome AF: 0.217 AC: 119891 AN: 552672 Hom.: 13783 Cov.: 0 AF XY: 0.215 AC XY: 64244 AN XY: 299376

African (AFR) AF: 0.0884 AC: 1407 AN: 15918

American (AMR) AF: 0.280 AC: 9759 AN: 34838

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 5286 AN: 20028

East Asian (EAS) AF: 0.184 AC: 5922 AN: 32256

South Asian (SAS) AF: 0.177 AC: 11119 AN: 62810

European-Finnish (FIN) AF: 0.261 AC: 8857 AN: 33906

Middle Eastern (MID) AF: 0.195 AC: 719 AN: 3690

European-Non Finnish (NFE) AF: 0.221 AC: 70351 AN: 318480

Other (OTH) AF: 0.210 AC: 6471 AN: 30746

GnomAD4 genome AF: 0.187 AC: 28391 AN: 152096 Hom.: 3004 Cov.: 31 AF XY: 0.189 AC XY: 14049 AN XY: 74334

African (AFR) AF: 0.0880 AC: 3654 AN: 41504

American (AMR) AF: 0.235 AC: 3585 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3468

East Asian (EAS) AF: 0.202 AC: 1045 AN: 5166

South Asian (SAS) AF: 0.178 AC: 859 AN: 4820

European-Finnish (FIN) AF: 0.253 AC: 2668 AN: 10564

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.220 AC: 14950 AN: 67978

Other (OTH) AF: 0.196 AC: 413 AN: 2110

Alfa AF: 0.208 Hom.: 10456

Bravo AF: 0.183

Asia WGS AF: 0.191 AC: 663 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.53
PhyloP100		-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: rs10876966; hg19: chr12-57543572; COSMIC: COSV54530616; COSMIC: COSV54530616;