11-68446521-C-T

Position:

chr11-68446521-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_002335.4(LRP5):c.4574C>T(p.Ala1525Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,754 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 110 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.511

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074311197).

BP6

Variant 11-68446521-C-T is Benign according to our data. Variant chr11-68446521-C-T is described in ClinVar as [Benign]. Clinvar id is 195672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68446521-C-T is described in Lovd as [Benign]. Variant chr11-68446521-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0107 (15642/1461422) while in subpopulation NFE AF= 0.0125 (13939/1111656). AF 95% confidence interval is 0.0124. There are 110 homozygotes in gnomad4_exome. There are 7482 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.4574C>T	p.Ala1525Val	missense_variant	22/23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRP5	ENST00000294304.12 linkuse as main transcript	c.4574C>T	p.Ala1525Val	missense_variant	22/23	1	NM_002335.4	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5 linkuse as main transcript	n.*3180C>T		non_coding_transcript_exon_variant	22/23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5 linkuse as main transcript	n.*3180C>T		3_prime_UTR_variant	22/23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000529702.1 linkuse as main transcript	c.242C>T	p.Ala81Val	missense_variant	3/4	3		ENSP00000435315.1	H0YE98

Frequencies

GnomAD3 genomes

AF:

0.00959

AC:

1460

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00489

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00911

GnomAD3 exomes

AF:

0.00770

AC:

1934

AN:

251260

Hom.:

AF XY:

0.00746

AC XY:

1013

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.00506

Gnomad ASJ exome

AF:

0.00794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00533

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.0107

AC:

15642

AN:

1461422

Hom.:

110

Cov.:

AF XY:

0.0103

AC XY:

7482

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.00959

Gnomad4 AMR exome

AF:

0.00537

Gnomad4 ASJ exome

AF:

0.00765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.00613

Gnomad4 NFE exome

AF:

0.0125

Gnomad4 OTH exome

AF:

0.00947

GnomAD4 genome

AF:

0.00958

AC:

1460

AN:

152332

Hom.:

Cov.:

AF XY:

0.00881

AC XY:

656

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0105

Gnomad4 AMR

AF:

0.0100

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00489

Gnomad4 NFE

AF:

0.0112

Gnomad4 OTH

AF:

0.00901

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.00986

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00864

AC:

ESP6500EA

AF:

0.00978

AC:

ExAC

AF:

0.00787

AC:

956

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0114

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	LRP5: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16956801) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2014	- -

Osteogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.32

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.58

REVEL

Benign

0.16

Sift

Benign

0.43

Sift4G

Benign

0.50

Polyphen

0.0060

Vest4

0.12

MVP

0.53

MPC

0.41

ClinPred

0.013

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.045

gMVP

0.22

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