11-68348021-A-G

Position:

chr11-68348021-A-G

Variant summary

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

The ENST00000294304.12(LRP5):c.266A>G(p.Gln89Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00951 in 1,614,176 control chromosomes in the GnomAD database, including 295 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q89Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0091 ( 32 hom., cov: 33)

Exomes 𝑓: 0.0096 ( 263 hom. )

Consequence

LRP5
ENST00000294304.12 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.99

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 1 (size 256) in uniprot entity LRP5_HUMAN there are 54 pathogenic changes around while only 6 benign (90%) 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=0.0024719536).

BP6

Variant 11-68348021-A-G is Benign according to our data. Variant chr11-68348021-A-G is described in ClinVar as [Benign]. Clinvar id is 195166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68348021-A-G is described in Lovd as [Benign]. Variant chr11-68348021-A-G is described in Lovd as [Likely_benign]. Variant chr11-68348021-A-G is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0748 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.266A>G	p.Gln89Arg	missense_variant	2/23	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.266A>G	p.Gln89Arg	missense_variant	2/23	1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5 linkuse as main transcript	c.266A>G	p.Gln89Arg	missense_variant, NMD_transcript_variant	2/23	1		ENSP00000436652

Frequencies

GnomAD3 genomes

AF:

0.00914

AC:

1391

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0810

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00541

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0195

AC:

4894

AN:

251332

Hom.:

189

AF XY:

0.0162

AC XY:

2202

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.0649

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0934

Gnomad SAS exome

AF:

0.00506

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00542

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.00955

AC:

13962

AN:

1461840

Hom.:

263

Cov.:

AF XY:

0.00898

AC XY:

6531

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00263

Gnomad4 AMR exome

AF:

0.0606

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0768

Gnomad4 SAS exome

AF:

0.00556

Gnomad4 FIN exome

AF:

0.00142

Gnomad4 NFE exome

AF:

0.00612

Gnomad4 OTH exome

AF:

0.0113

GnomAD4 genome

AF:

0.00914

AC:

1393

AN:

152336

Hom.:

Cov.:

AF XY:

0.00944

AC XY:

703

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00243

Gnomad4 AMR

AF:

0.0284

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0812

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00541

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00796

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.0174

AC:

2109

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00480

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31169861, 30513533, 28378289, 16115379, 21528003, 17955262, 22511589) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2014	- -

Osteogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.36

DEOGEN2

Benign

0.27

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.36

REVEL

Benign

0.26

Sift

Benign

0.88

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.12

MPC

0.44

ClinPred

0.021

GERP RS

4.5

Varity_R

0.11

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