12-57138780-G-A

Position:

• chr12-57138780-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002332.3(LRP1):​c.190+199G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 152,176 control chromosomes in the GnomAD database, including 873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.063 (873 hom., cov: 32)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.221

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-57138780-G-A is Benign according to our data. Variant chr12-57138780-G-A is described in ClinVar as [Benign]. Clinvar id is 1224154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1	NM_002332.3	c.190+199G>A		intron_variant		ENST00000243077.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1	ENST00000243077.8	c.190+199G>A		intron_variant		1	NM_002332.3	P1
LRP1	ENST00000338962.8	c.190+199G>A		intron_variant		1
LRP1	ENST00000553277.5	c.190+199G>A		intron_variant		1
LRP1	ENST00000554174.1	c.190+199G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0626 AC: 9525 AN: 152058 Hom.: 867 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.0459

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

GnomAD4 genome AF: 0.0628 AC: 9550 AN: 152176 Hom.: 873 Cov.: 32 AF XY: 0.0618 AC XY: 4602 AN XY: 74406

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.0208

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.0454

Alfa AF: 0.0322 Hom.: 47

Bravo AF: 0.0672

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.2
DANN	Benign	0.31

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: rs34484591; hg19: chr12-57532563;