chr12-57149789-C-T

Position:

• chr12-57149789-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000243077.8(LRP1):​c.841+4299C>T variant causes a intron 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 ENST00000243077.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
LRP1	NM_002332.3	c.841+4299C>T		intron_variant		ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000338962.8	c.*771C>T		3_prime_UTR_variant	7/7	1		ENSP00000341264
LRP1	ENST00000553277.5	c.*60C>T		3_prime_UTR_variant	7/7	1		ENSP00000451449
LRP1	ENST00000243077.8	c.841+4299C>T		intron_variant		1	NM_002332.3	ENSP00000243077	P1
LRP1	ENST00000554174.1	c.841+4299C>T		intron_variant		1		ENSP00000451737

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

Gnomad4 AFR exome AF: 0.0884

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.210

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

Gnomad4 AFR AF: 0.0880

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.196

Alfa AF: 0.213 Hom.: 4949

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs10876966; hg19: chr12-57543572; COSMIC: COSV54530616; COSMIC: COSV54530616;