rs545382

Positions:

• chr11-68403545-T-A
• chr11-68403545-T-C
• chr11-68403545-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_002335.4(LRP5):​c.1647T>A​(p.Phe549Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F549F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP5 NM_002335.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a repeat LDL-receptor class B 9 (size 42) in uniprot entity LRP5_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) 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). 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.1647T>A	p.Phe549Leu	missense_variant	8/23	ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.1647T>A	p.Phe549Leu	missense_variant	8/23	1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.*59T>A		3_prime_UTR_variant, NMD_transcript_variant	7/23	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	0.0000068	P
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.55	P
Vest4		0.82
MutPred		0.61		Gain of catalytic residue at F549 (P = 0.0707);
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		-2.2
Varity_R		0.74
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs545382; hg19: chr11-68171013;