NM_002335.4:c.1585-118G>T

Variant names:

• chr11-68403365-G-T
• rs686921
• NM_002335.4:c.1585-118G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.253
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• bone mineral density quantitative trait locus 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• exudative vitreoretinopathy 4

  Inheritance: AD, SD, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• osteoporosis-pseudoglioma syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant osteosclerosis, Worth type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• polycystic liver disease 4 with or without kidney cysts

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant osteopetrosis 1

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• exudative vitreoretinopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyperostosis corticalis generalisata

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteosclerosis-developmental delay-craniosynostosis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• polycystic liver disease 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	c.1585-118G>T		intron_variant	Intron 7 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.1585-118G>T		intron_variant	Intron 7 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.1413-118G>T		intron_variant	Intron 6 of 22	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104271 AN: 152050 Hom.: 37442 Cov.: 31

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

African (AFR) AF: 0.463 AC: 8239 AN: 17784

American (AMR) AF: 0.735 AC: 25174 AN: 34232

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 14850 AN: 20308

East Asian (EAS) AF: 0.734 AC: 23761 AN: 32358

South Asian (SAS) AF: 0.834 AC: 53490 AN: 64120

European-Finnish (FIN) AF: 0.914 AC: 41087 AN: 44976

Middle Eastern (MID) AF: 0.706 AC: 2273 AN: 3218

European-Non Finnish (NFE) AF: 0.752 AC: 309238 AN: 411168

Other (OTH) AF: 0.740 AC: 24862 AN: 33588

GnomAD4 genome AF: 0.685 AC: 104304 AN: 152168 Hom.: 37449 Cov.: 31 AF XY: 0.698 AC XY: 51915 AN XY: 74400

African (AFR) AF: 0.467 AC: 19397 AN: 41494

American (AMR) AF: 0.714 AC: 10918 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2593 AN: 3472

East Asian (EAS) AF: 0.782 AC: 4036 AN: 5162

South Asian (SAS) AF: 0.840 AC: 4053 AN: 4824

European-Finnish (FIN) AF: 0.927 AC: 9842 AN: 10618

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.756 AC: 51422 AN: 68000

Other (OTH) AF: 0.676 AC: 1427 AN: 2110

Alfa AF: 0.668 Hom.: 2655

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

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
PhyloP100		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs686921; hg19: chr11-68170833;