11-68449010-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002335.4(LRP5):c.4788C>T(p.Thr1596=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,599,766 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1596T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 32)
  • Exomes 𝑓: 0.018 (304 hom.)
• Consequence: LRP5 NM_002335.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.21

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-68449010-C-T is Benign according to our data. Variant chr11-68449010-C-T is described in ClinVar as [Benign]. Clinvar id is 258641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68449010-C-T is described in Lovd as [Benign]. Variant chr11-68449010-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1997/152102) while in subpopulation NFE AF= 0.0196 (1331/67970). AF 95% confidence interval is 0.0187. There are 23 homozygotes in gnomad4. There are 906 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.4788C>T	p.Thr1596=	synonymous_variant	23/23	ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.4788C>T	p.Thr1596=	synonymous_variant	23/23	1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.*3394C>T		3_prime_UTR_variant, NMD_transcript_variant	23/23	1
LRP5	ENST00000529702.1	c.459C>T	p.Thr153=	synonymous_variant	4/4	3
LRP5	ENST00000529481.1	n.379C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1996 AN: 151986 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.0717

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0183

GnomAD3 exomes AF: 0.0153 AC: 3632 AN: 236966 Hom.: 46 AF XY: 0.0155 AC XY: 1994 AN XY: 128810

Gnomad AFR exome AF: 0.00262

Gnomad AMR exome AF: 0.00983

Gnomad ASJ exome AF: 0.0679

Gnomad EAS exome AF: 0.00225

Gnomad SAS exome AF: 0.00324

Gnomad FIN exome AF: 0.00754

Gnomad NFE exome AF: 0.0205

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0180 AC: 26031 AN: 1447664 Hom.: 304 Cov.: 33 AF XY: 0.0178 AC XY: 12836 AN XY: 720100

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00993

Gnomad4 ASJ exome AF: 0.0718

Gnomad4 EAS exome AF: 0.00260

Gnomad4 SAS exome AF: 0.00350

Gnomad4 FIN exome AF: 0.00759

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0131 AC: 1997 AN: 152102 Hom.: 23 Cov.: 32 AF XY: 0.0122 AC XY: 906 AN XY: 74358

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.00864

Gnomad4 ASJ AF: 0.0717

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.00313

Gnomad4 FIN AF: 0.00603

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.0181

Alfa AF: 0.0174 Hom.: 8

Bravo AF: 0.0138

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2019	This variant is associated with the following publications: (PMID: 15981244, 12579474, 16234968, 18721193) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:2

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	-	- -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.13
Dann	Benign	0.62
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: rs113442867; hg19: chr11-68216478;