11-68312730-C-A

Position:

chr11-68312730-C-A

Variant summary

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

The NM_002335.4(LRP5):c.16C>A(p.Pro6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,052,528 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 5 hom., cov: 31)

Exomes 𝑓: 0.00030 ( 9 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.171

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:

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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=0.010892689).

BP6

Variant 11-68312730-C-A is Benign according to our data. Variant chr11-68312730-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 499142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00292 (424/145040) while in subpopulation AMR AF= 0.0263 (387/14732). AF 95% confidence interval is 0.0241. There are 5 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.16C>A	p.Pro6Thr	missense_variant	1/23	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.16C>A	p.Pro6Thr	missense_variant	1/23	1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5 linkuse as main transcript	c.16C>A	p.Pro6Thr	missense_variant, NMD_transcript_variant	1/23	1		ENSP00000436652

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

425

AN:

144936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000448

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0264

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000401

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000138

Gnomad OTH

AF:

0.00349

GnomAD3 exomes

AF:

0.00872

AC:

125

AN:

14342

Hom.:

AF XY:

0.00634

AC XY:

AN XY:

8672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0462

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00870

GnomAD4 exome

AF:

0.000301

AC:

273

AN:

907488

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

112

AN XY:

432226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0371

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000380

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000631

Gnomad4 OTH exome

AF:

0.000749

GnomAD4 genome

AF:

0.00292

AC:

424

AN:

145040

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

226

AN XY:

70618

show subpopulations

Gnomad4 AFR

AF:

0.000447

Gnomad4 AMR

AF:

0.0263

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000403

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000138

Gnomad4 OTH

AF:

0.00345

Alfa

AF:

0.00228

Hom.:

Bravo

AF:

0.00543

ExAC

AF:

0.000209

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 11, 2017

- -

Osteogenesis imperfecta

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.27

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.35

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.050

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Polyphen

0.0

Vest4

0.23

MVP

0.47

MPC

0.46

ClinPred

0.029

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.089

gMVP

0.31

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