11-68429493-C-T

Position:

• chr11-68429493-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002335.4(LRP5):​c.3638-82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,581,846 control chromosomes in the GnomAD database, including 83,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10349 hom., cov: 31)
  • Exomes 𝑓: 0.32 (73636 hom.)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-68429493-C-T is Benign according to our data. Variant chr11-68429493-C-T is described in ClinVar as [Benign]. Clinvar id is 1286716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.3638-82C>T		intron_variant		ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.3638-82C>T		intron_variant		1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*2244-82C>T		intron_variant		1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53221 AN: 151960 Hom.: 10324 Cov.: 31

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.362

GnomAD4 exome AF: 0.316 AC: 451234 AN: 1429766 Hom.: 73636 AF XY: 0.312 AC XY: 222331 AN XY: 712940

Gnomad4 AFR exome AF: 0.503

Gnomad4 AMR exome AF: 0.296

Gnomad4 ASJ exome AF: 0.317

Gnomad4 EAS exome AF: 0.317

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.325

GnomAD4 genome AF: 0.350 AC: 53292 AN: 152080 Hom.: 10349 Cov.: 31 AF XY: 0.339 AC XY: 25221 AN XY: 74352

Gnomad4 AFR AF: 0.493

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.266

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.361

Alfa AF: 0.329 Hom.: 5435

Bravo AF: 0.379

Asia WGS AF: 0.278 AC: 968 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.092
DANN	Benign	0.57

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: rs607887; hg19: chr11-68196961; COSMIC: COSV53717587;