12-57145319-C-G

Position:

• chr12-57145319-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_002332.3(LRP1):​c.670C>G​(p.Pro224Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRP1 NM_002332.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.57

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-AS (HGNC:51694): (LRP1 antisense RNA)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP1. . Gene score misZ 8.2463 (greater than the threshold 3.09). Trascript score misZ 12.011 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia, atrophoderma vermiculata, keratosis pilaris atrophicans, keratosis follicularis spinulosa decalvans.
• PP5: Variant 12-57145319-C-G is Pathogenic according to our data. Variant chr12-57145319-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2691745.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19619215). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP1	NM_002332.3	c.670C>G	p.Pro224Ala	missense_variant	6/89	ENST00000243077.8	NP_002323.2
LRP1-AS	NR_131938.1	n.182-236G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.670C>G	p.Pro224Ala	missense_variant	6/89	1	NM_002332.3	ENSP00000243077	P1
LRP1-AS	ENST00000555461.1	n.182-236G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental dysplasia of the hip 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.80
DEOGEN2	Benign	0.10	.;T;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.55	.;N;N;.
MutationTaster	Benign	0.92	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.48	N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.94	T;T;T;T
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.70	P;B;.;B
Vest4		0.50
MutPred		0.30		Gain of catalytic residue at V219 (P = 2e-04);Gain of catalytic residue at V219 (P = 2e-04);Gain of catalytic residue at V219 (P = 2e-04);Gain of catalytic residue at V219 (P = 2e-04);
MVP		0.44
ClinPred		0.37	T
GERP RS		5.1
Varity_R		0.094
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-57539102;