NM_002332.3:c.9783G>A

Variant names:

• chr12-57199318-G-A
• rs1140648
• NM_002332.3:c.9783G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002332.3(LRP1):​c.9783G>A​(p.Thr3261Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 1,613,320 control chromosomes in the GnomAD database, including 355,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25991 hom., cov: 34)
  • Exomes 𝑓: 0.67 (329878 hom.)
• Consequence: LRP1 NM_002332.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.57
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-57199318-G-A is Benign according to our data. Variant chr12-57199318-G-A is described in ClinVar as Benign. ClinVar VariationId is 1300111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002332.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	NM_002332.3	MANE Select	c.9783G>A	p.Thr3261Thr	synonymous	Exon 61 of 89	NP_002323.2	Q07954-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	ENST00000243077.8	TSL:1 MANE Select	c.9783G>A	p.Thr3261Thr	synonymous	Exon 61 of 89	ENSP00000243077.3	Q07954-1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85465 AN: 152040 Hom.: 25990 Cov.: 34

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.591

GnomAD2 exomes AF: 0.621 AC: 155745 AN: 250866 AF XY: 0.644

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.548

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.650

GnomAD4 exome AF: 0.667 AC: 974371 AN: 1461162 Hom.: 329878 Cov.: 56 AF XY: 0.674 AC XY: 489665 AN XY: 726920

African (AFR) AF: 0.303 AC: 10142 AN: 33480

American (AMR) AF: 0.482 AC: 21569 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 17848 AN: 26132

East Asian (EAS) AF: 0.587 AC: 23285 AN: 39696

South Asian (SAS) AF: 0.785 AC: 67707 AN: 86250

European-Finnish (FIN) AF: 0.600 AC: 31746 AN: 52908

Middle Eastern (MID) AF: 0.657 AC: 3787 AN: 5764

European-Non Finnish (NFE) AF: 0.683 AC: 758938 AN: 1111838

Other (OTH) AF: 0.652 AC: 39349 AN: 60378

GnomAD4 genome AF: 0.562 AC: 85474 AN: 152158 Hom.: 25991 Cov.: 34 AF XY: 0.564 AC XY: 41959 AN XY: 74368

African (AFR) AF: 0.316 AC: 13131 AN: 41504

American (AMR) AF: 0.579 AC: 8855 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2349 AN: 3468

East Asian (EAS) AF: 0.542 AC: 2795 AN: 5158

South Asian (SAS) AF: 0.766 AC: 3696 AN: 4826

European-Finnish (FIN) AF: 0.607 AC: 6427 AN: 10596

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.680 AC: 46260 AN: 67994

Other (OTH) AF: 0.593 AC: 1251 AN: 2110

Alfa AF: 0.629 Hom.: 47873

Bravo AF: 0.538

Asia WGS AF: 0.571 AC: 1989 AN: 3478

EpiCase AF: 0.690

EpiControl AF: 0.687

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Keratosis pilaris (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.043
DANN	Benign	0.90
PhyloP100		-8.6
Mutation Taster		=86/14	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: rs1140648; hg19: chr12-57593101; COSMIC: COSV54502404; COSMIC: COSV54502404;