11-68403545-T-G

Position:

• chr11-68403545-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001291902.2(LRP5):​c.-291T>G variant causes a 5 prime UTR premature start codon gain 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP5 NM_001291902.2 5_prime_UTR_premature_start_codon_gain
• 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.1647T>G	p.Phe549Leu	missense_variant	8/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.1647T>G	p.Phe549Leu	missense_variant	8/23	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*59T>G		non_coding_transcript_exon_variant	7/23	1		ENSP00000436652.1
LRP5	ENST00000529993.5	n.*59T>G		3_prime_UTR_variant	7/23	1		ENSP00000436652.1

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	0.81	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.1	M
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)		0.0		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

Other links and lift over

dbSNP: rs545382; hg19: chr11-68171013;