11-68406721-G-A

Position:

chr11-68406721-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000294304.12(LRP5):c.1999G>A(p.Val667Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,614,070 control chromosomes in the GnomAD database, including 1,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 140 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1802 hom. )

Consequence

LRP5
ENST00000294304.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:13O:2

Conservation

PhyloP100: 7.87

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 -17 ACMG points.

PM1

In a region_of_interest Beta-propeller 3 (size 259) in uniprot entity LRP5_HUMAN there are 46 pathogenic changes around while only 7 benign (87%) in ENST00000294304.12

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=0.0044097304).

BP6

Variant 11-68406721-G-A is Benign according to our data. Variant chr11-68406721-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 6276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68406721-G-A is described in Lovd as [Pathogenic]. Variant chr11-68406721-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-68406721-G-A is described in Lovd as [Benign]. Variant chr11-68406721-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.1999G>A	p.Val667Met	missense_variant	9/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 linkuse as main transcript	c.1999G>A	p.Val667Met	missense_variant	9/23	1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5 linkuse as main transcript	c.*605G>A		3_prime_UTR_variant, NMD_transcript_variant	9/23	1		ENSP00000436652

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5287

AN:

152158

Hom.:

140

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00975

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0427

Gnomad ASJ

AF:

0.0876

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0253

Gnomad FIN

AF:

0.00990

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0517

Gnomad OTH

AF:

0.0540

GnomAD3 exomes

AF:

0.0381

AC:

9565

AN:

251330

Hom.:

265

AF XY:

0.0388

AC XY:

5273

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00800

Gnomad AMR exome

AF:

0.0325

Gnomad ASJ exome

AF:

0.0932

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0264

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.0525

Gnomad OTH exome

AF:

0.0548

GnomAD4 exome

AF:

0.0464

AC:

67886

AN:

1461794

Hom.:

1802

Cov.:

AF XY:

0.0461

AC XY:

33492

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00890

Gnomad4 AMR exome

AF:

0.0348

Gnomad4 ASJ exome

AF:

0.0924

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0269

Gnomad4 FIN exome

AF:

0.0130

Gnomad4 NFE exome

AF:

0.0515

Gnomad4 OTH exome

AF:

0.0457

GnomAD4 genome

AF:

0.0347

AC:

5287

AN:

152276

Hom.:

140

Cov.:

AF XY:

0.0337

AC XY:

2507

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00972

Gnomad4 AMR

AF:

0.0426

Gnomad4 ASJ

AF:

0.0876

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0257

Gnomad4 FIN

AF:

0.00990

Gnomad4 NFE

AF:

0.0517

Gnomad4 OTH

AF:

0.0534

Alfa

AF:

0.0531

Hom.:

581

Bravo

AF:

0.0375

TwinsUK

AF:

0.0515

AC:

191

ALSPAC

AF:

0.0477

AC:

184

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.0559

AC:

480

ExAC

AF:

0.0375

AC:

4557

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0580

EpiControl

AF:

0.0569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:13Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30283887, 28222408, 15077203, 18026682, 18349089, 22025579, 18058054, 11719191, 17307038, 22511589, 21116122) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Osteoporosis with pseudoglioma

Pathogenic:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 16, 2001	- -
not provided, no classification provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2015	- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2014

- -

Osteogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2022

- -

Increased bone mineral density

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 31, 2021

- -

Osteoporosis;C0432252:Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 1;C1851402:Exudative vitreoretinopathy 1;C1866079:Bone mineral density quantitative trait locus 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0044

MetaSVM

Uncertain

0.0064

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.55

Sift

Benign

0.039

Sift4G

Benign

0.093

Polyphen

0.99

Vest4

0.17

MPC

0.43

ClinPred

0.049

GERP RS

4.1

Varity_R

0.13

gMVP

0.71

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