Genetic Variant LRP5:c.1585-118G>T (chr11-68403365-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_002335.4(LRP5):c.1585-118G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 813,920 control chromosomes in the GnomAD database, including 230,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 37449 hom., cov: 31)

Exomes 𝑓: 0.76 ( 193411 hom. )

Consequence

LRP5
NM_002335.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.253

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 11-68403365-G-T is Benign according to our data. Variant chr11-68403365-G-T is described in ClinVar as [Benign]. Clinvar id is 1241533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.1585-118G>T		intron_variant	Intron 7 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.1585-118G>T		intron_variant	Intron 7 of 22	1	NM_002335.4	ENSP00000294304.6		O75197
LRP5	ENST00000529993.5 link	n.1413-118G>T		intron_variant	Intron 6 of 22	1		ENSP00000436652.1		E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.686

AC:

104271

AN:

152050

Hom.:

37442

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.461

Gnomad AMR

AF:

0.714

Gnomad ASJ

AF:

0.747

Gnomad EAS

AF:

0.782

Gnomad SAS

AF:

0.840

Gnomad FIN

AF:

0.927

Gnomad MID

AF:

0.674

Gnomad NFE

AF:

0.756

Gnomad OTH

AF:

0.675

GnomAD4 exome

AF:

0.760

AC:

502974

AN:

661752

Hom.:

193411

AF XY:

0.765

AC XY:

267148

AN XY:

349086

show subpopulations

Gnomad4 AFR exome

AF:

0.463

Gnomad4 AMR exome

AF:

0.735

Gnomad4 ASJ exome

AF:

0.731

Gnomad4 EAS exome

AF:

0.734

Gnomad4 SAS exome

AF:

0.834

Gnomad4 FIN exome

AF:

0.914

Gnomad4 NFE exome

AF:

0.752

Gnomad4 OTH exome

AF:

0.740

GnomAD4 genome

AF:

0.685

AC:

104304

AN:

152168

Hom.:

37449

Cov.:

AF XY:

0.698

AC XY:

51915

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.467

Gnomad4 AMR

AF:

0.714

Gnomad4 ASJ

AF:

0.747

Gnomad4 EAS

AF:

0.782

Gnomad4 SAS

AF:

0.840

Gnomad4 FIN

AF:

0.927

Gnomad4 NFE

AF:

0.756

Gnomad4 OTH

AF:

0.676

Alfa

AF:

0.683

Hom.:

2574

Bravo

AF:

0.653

Asia WGS

AF:

0.787

AC:

2736

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.8

DANN

Benign

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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