NM_002335.4:c.1412+8G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002335.4(LRP5):c.1412+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,610,102 control chromosomes in the GnomAD database, including 21,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1720 hom., cov: 33)

Exomes 𝑓: 0.16 ( 19662 hom. )

Consequence

LRP5
NM_002335.4 splice_region, intron

Scores

Splicing: ADA: 0.0001451

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.538

Variant links:

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]

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 11-68386720-G-A is Benign according to our data. Variant chr11-68386720-G-A is described in ClinVar as [Benign]. Clinvar id is 258633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68386720-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.1412+8G>A		splice_region_variant, intron_variant	Intron 6 of 22	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12 link	c.1412+8G>A		splice_region_variant, intron_variant	Intron 6 of 22	1	NM_002335.4	ENSP00000294304.6		O75197
LRP5	ENST00000529993.5 link	n.1412+8G>A		splice_region_variant, intron_variant	Intron 6 of 22	1		ENSP00000436652.1		E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22391

AN:

152170

Hom.:

1719

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.0606

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.153

GnomAD3 exomes

AF:

0.136

AC:

33041

AN:

242994

Hom.:

2391

AF XY:

0.133

AC XY:

17599

AN XY:

132474

show subpopulations

Gnomad AFR exome

AF:

0.139

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.165

Gnomad EAS exome

AF:

0.111

Gnomad SAS exome

AF:

0.0584

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.150

GnomAD4 exome

AF:

0.160

AC:

232867

AN:

1457814

Hom.:

19662

Cov.:

AF XY:

0.157

AC XY:

113760

AN XY:

724958

show subpopulations

Gnomad4 AFR exome

AF:

0.129

Gnomad4 AMR exome

AF:

0.125

Gnomad4 ASJ exome

AF:

0.168

Gnomad4 EAS exome

AF:

0.0817

Gnomad4 SAS exome

AF:

0.0597

Gnomad4 FIN exome

AF:

0.107

Gnomad4 NFE exome

AF:

0.175

Gnomad4 OTH exome

AF:

0.154

GnomAD4 genome

AF:

0.147

AC:

22411

AN:

152288

Hom.:

1720

Cov.:

AF XY:

0.141

AC XY:

10533

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.126

Gnomad4 ASJ

AF:

0.160

Gnomad4 EAS

AF:

0.104

Gnomad4 SAS

AF:

0.0611

Gnomad4 FIN

AF:

0.101

Gnomad4 NFE

AF:

0.171

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.163

Hom.:

668

Bravo

AF:

0.153

Asia WGS

AF:

0.0830

AC:

291

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.40

DANN

Benign

0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over