rs80358316

Positions:

chr11-68411509-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PS1_ModeratePM1PM2PP2PP5BS1_Supporting

The NM_002335.4(LRP5):c.2392A>G(p.Thr798Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LRP5
NM_002335.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

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 Likely_pathogenic. Variant got 7 ACMG points.

PS1

Transcript NM_002335.4 (LRP5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a region_of_interest Beta-propeller 3 (size 259) in uniprot entity LRP5_HUMAN there are 34 pathogenic changes around while only 1 benign (97%) 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). The gene has 71 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. GenCC has associacion of the 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.

PP5

Variant 11-68411509-A-G is Pathogenic according to our data. Variant chr11-68411509-A-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000394 (6/152328) while in subpopulation EAS AF= 0.00116 (6/5178). AF 95% confidence interval is 0.000505. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.2392A>G	p.Thr798Ala	missense_variant	11/23	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRP5	ENST00000294304.12 link	c.2392A>G	p.Thr798Ala	missense_variant	11/23	1	NM_002335.4	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5 link	n.*998A>G		non_coding_transcript_exon_variant	11/23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5 link	n.*998A>G		3_prime_UTR_variant	11/23	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000528714.1 link	n.186A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250846

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461404

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

Eigen

Benign

0.041

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.78

Sift

Benign

0.063

Sift4G

Benign

0.13

Polyphen

0.074

Vest4

0.74

MVP

1.0

MPC

0.48

ClinPred

0.81

GERP RS

4.5

Varity_R

0.12

gMVP

0.47

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over