11-68312693-GC-G

Variant names:

• chr11-68312693-GC-G
• rs763941232
• NM_002335.4:c.-19delC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002335.4(LRP5):​c.-19delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00852 in 993,782 control chromosomes in the GnomAD database, including 45 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (5 hom., cov: 30)
  • Exomes 𝑓: 0.0088 (40 hom.)
• Consequence: LRP5 NM_002335.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.493

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 -9 ACMG points.

• BP6: Variant 11-68312693-GC-G is Benign according to our data. Variant chr11-68312693-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287479.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00667 (966/144788) while in subpopulation NFE AF= 0.0108 (703/65190). AF 95% confidence interval is 0.0101. There are 5 homozygotes in gnomad4. There are 417 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.-19delC		5_prime_UTR_variant	Exon 1 of 23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304	c.-19delC		5_prime_UTR_variant	Exon 1 of 23	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.-19delC		non_coding_transcript_exon_variant	Exon 1 of 23	1		ENSP00000436652.1
LRP5	ENST00000529993.5	n.-19delC		5_prime_UTR_variant	Exon 1 of 23	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 966 AN: 144672 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00225

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00168

Gnomad FIN AF: 0.00430

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00502

GnomAD3 exomes AF: 0.00220 AC: 2 AN: 908 Hom.: 0 AF XY: 0.00187 AC XY: 1 AN XY: 534

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00524

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00883 AC: 7498 AN: 848994 Hom.: 40 Cov.: 16 AF XY: 0.00867 AC XY: 3447 AN XY: 397760

Gnomad4 AFR exome AF: 0.000817

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.000214

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.00648

Gnomad4 NFE exome AF: 0.00928

Gnomad4 OTH exome AF: 0.00698

GnomAD4 genome AF: 0.00667 AC: 966 AN: 144788 Hom.: 5 Cov.: 30 AF XY: 0.00591 AC XY: 417 AN XY: 70508

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.0180

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00168

Gnomad4 FIN AF: 0.00430

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00496

Alfa AF: 0.00956 Hom.: 2

Bravo AF: 0.00594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2019	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2024	LRP5: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2016	- -

not specified Benign:1

Likely benign, flagged submission

clinical testing

GeneDx

Aug 17, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763941232; hg19: chr11-68080161;