chr11-68425162-C-T

Position:

• chr11-68425162-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002335.4(LRP5):​c.3297C>T​(p.Asp1099Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,613,646 control chromosomes in the GnomAD database, including 1,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (726 hom., cov: 32)
  • Exomes 𝑓: 0.017 (756 hom.)
• Consequence: LRP5 NM_002335.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.52

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 11-68425162-C-T is Benign according to our data. Variant chr11-68425162-C-T is described in ClinVar as [Benign]. Clinvar id is 258637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68425162-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.3297C>T	p.Asp1099Asp	synonymous_variant	15/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.3297C>T	p.Asp1099Asp	synonymous_variant	15/23	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*1903C>T		non_coding_transcript_exon_variant	15/23	1		ENSP00000436652.1
LRP5	ENST00000529993.5	n.*1903C>T		3_prime_UTR_variant	15/23	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.0593 AC: 9019 AN: 152114 Hom.: 723 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0493

GnomAD3 exomes AF: 0.0223 AC: 5571 AN: 250344 Hom.: 300 AF XY: 0.0189 AC XY: 2562 AN XY: 135496

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00758

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0168 AC: 24543 AN: 1461414 Hom.: 756 Cov.: 32 AF XY: 0.0159 AC XY: 11581 AN XY: 727056

Gnomad4 AFR exome AF: 0.183

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.000857

Gnomad4 SAS exome AF: 0.00762

Gnomad4 FIN exome AF: 0.00541

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0247

GnomAD4 genome AF: 0.0594 AC: 9047 AN: 152232 Hom.: 726 Cov.: 32 AF XY: 0.0561 AC XY: 4179 AN XY: 74448

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0295 Hom.: 209

Bravo AF: 0.0667

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.8
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs17149104; hg19: chr11-68192630;