rs729635

Positions:

• chr11-68344292-A-C
• chr11-68344292-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000294304.12(LRP5):​c.92-3555A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,148 control chromosomes in the GnomAD database, including 1,098 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1098 hom., cov: 32)
• Consequence: LRP5 ENST00000294304.12 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.92-3555A>C		intron_variant		ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.92-3555A>C		intron_variant		1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5	c.92-3555A>C		intron_variant, NMD_transcript_variant		1		ENSP00000436652

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15727 AN: 152030 Hom.: 1095 Cov.: 32

Gnomad AFR AF: 0.0620

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.0866

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.121

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.103 AC: 15747 AN: 152148 Hom.: 1098 Cov.: 32 AF XY: 0.103 AC XY: 7666 AN XY: 74380

Gnomad4 AFR AF: 0.0622

Gnomad4 AMR AF: 0.244

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.0149

Gnomad4 SAS AF: 0.0862

Gnomad4 FIN AF: 0.0491

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.120

Alfa AF: 0.116 Hom.: 1664

Bravo AF: 0.121

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.99
DANN	Benign	0.30

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: rs729635; hg19: chr11-68111760;