rs4988319

Variant names:

• chr11-68386720-G-A
• rs4988319
• NM_002335.4:c.1412+8G>A

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.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:8
• Conservation: PhyloP100: -0.538
• Publications: 15 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
• LRP5-related exudative vitreoretinopathy

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• exudative vitreoretinopathy 4

  Inheritance: Unknown, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• autosomal dominant osteosclerosis, Worth type

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

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

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• 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=-0.72).
• BP6: Variant 11-68386720-G-A is Benign according to our data. Variant chr11-68386720-G-A is described in ClinVar as Benign. ClinVar VariationId is 258633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002335.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.1412+8G>A		splice_region intron	N/A	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.-354+8G>A		splice_region intron	N/A	NP_001278831.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	ENST00000294304.12	TSL:1 MANE Select	c.1412+8G>A		splice_region intron	N/A	ENSP00000294304.6	O75197
	LRP5	ENST00000529993.5	TSL:1	n.1412+8G>A		splice_region intron	N/A	ENSP00000436652.1	E9PHY1
	LRP5	ENST00000909991.1		c.1412+8G>A		splice_region intron	N/A	ENSP00000580050.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22391 AN: 152170 Hom.: 1719 Cov.: 33

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

GnomAD2 exomes AF: 0.136 AC: 33041 AN: 242994 AF XY: 0.133

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 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.: 35 AF XY: 0.157 AC XY: 113760 AN XY: 724958

African (AFR) AF: 0.129 AC: 4308 AN: 33426

American (AMR) AF: 0.125 AC: 5560 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4367 AN: 26040

East Asian (EAS) AF: 0.0817 AC: 3239 AN: 39628

South Asian (SAS) AF: 0.0597 AC: 5143 AN: 86122

European-Finnish (FIN) AF: 0.107 AC: 5573 AN: 51954

Middle Eastern (MID) AF: 0.117 AC: 671 AN: 5734

European-Non Finnish (NFE) AF: 0.175 AC: 194747 AN: 1110156

Other (OTH) AF: 0.154 AC: 9259 AN: 60230

GnomAD4 genome AF: 0.147 AC: 22411 AN: 152288 Hom.: 1720 Cov.: 33 AF XY: 0.141 AC XY: 10533 AN XY: 74470

African (AFR) AF: 0.137 AC: 5704 AN: 41558

American (AMR) AF: 0.126 AC: 1934 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3472

East Asian (EAS) AF: 0.104 AC: 538 AN: 5180

South Asian (SAS) AF: 0.0611 AC: 295 AN: 4828

European-Finnish (FIN) AF: 0.101 AC: 1073 AN: 10620

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11642 AN: 68012

Other (OTH) AF: 0.152 AC: 321 AN: 2116

Alfa AF: 0.163 Hom.: 668

Bravo AF: 0.153

Asia WGS AF: 0.0830 AC: 291 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.40
DANN	Benign	0.87
PhyloP100		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4988319; hg19: chr11-68154188; COSMIC: COSV53722367;