Variant chr11-68348188-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_002335.4(LRP5):c.433C>T(p.Leu145Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 1.67

Variant links:

Genes affected

LRP5 (HGNC:6697): (LDL receptor related protein 5) This gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with type 1 diabetes mellitus in humans. This protein plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene. Mutations in this gene also cause familial exudative vitreoretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

LRP5 links:

LRP5 (HGNC:):

LRP5 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a repeat LDL-receptor class B 2 (size 42) in uniprot entity LRP5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002335.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP5. . Gene score misZ 1.6684 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with exudative vitreoretinopathy 4, polycystic liver disease 4 with or without kidney cysts, polycystic liver disease 1, exudative vitreoretinopathy, osteosclerosis-developmental delay-craniosynostosis syndrome, bone mineral density quantitative trait locus 1, autosomal dominant osteopetrosis 1, hyperostosis corticalis generalisata, osteoporosis-pseudoglioma syndrome, autosomal dominant osteosclerosis, Worth type, inherited retinal dystrophy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 11-68348188-C-T is Pathogenic according to our data. Variant chr11-68348188-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6292.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-68348188-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.433C>T	p.Leu145Phe	missense_variant	2/23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 linkuse as main transcript	c.433C>T	p.Leu145Phe	missense_variant	2/23	1	NM_002335.4	ENSP00000294304.6		O75197
LRP5	ENST00000529993.5 linkuse as main transcript	n.433C>T		non_coding_transcript_exon_variant	2/23	1		ENSP00000436652.1		E9PHY1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460300

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Osteoporosis with pseudoglioma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

Exudative vitreoretinopathy 4, autosomal dominant

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.95

MutPred

0.88

Loss of catalytic residue at L145 (P = 0.0928);

MVP

0.95

MPC

1.3

ClinPred

0.95

GERP RS

3.7

Varity_R

0.85

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over