rs3736228

Variant names:

• chr11-68433827-C-T
• rs3736228
• NM_002335.4:c.3989C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_002335.4(LRP5):​c.3989C>T​(p.Ala1330Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,611,778 control chromosomes in the GnomAD database, including 17,351 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1330A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1182 hom., cov: 33)
  • Exomes 𝑓: 0.14 (16169 hom.)
• Consequence: LRP5 NM_002335.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.478
• Publications: 236 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 -19 ACMG points.

• PP2: Missense variant in the LRP5 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 71 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 1.6684 (below the threshold of 3.09). Trascript score misZ: 3.6986 (above the threshold of 3.09). GenCC associations: The gene is linked to exudative vitreoretinopathy 4, autosomal dominant osteopetrosis 1, osteoporosis-pseudoglioma syndrome, autosomal dominant osteosclerosis, Worth type, polycystic liver disease 4 with or without kidney cysts, bone mineral density quantitative trait locus 1, osteosclerosis-developmental delay-craniosynostosis syndrome, hyperostosis corticalis generalisata, exudative vitreoretinopathy, polycystic liver disease 1, inherited retinal dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020527542).
• BP6: Variant 11-68433827-C-T is Benign according to our data. Variant chr11-68433827-C-T is described in ClinVar as Benign. ClinVar VariationId is 258640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.3989C>T	p.Ala1330Val	missense	Exon 18 of 23	NP_002326.2
	LRP5	NM_001291902.2		c.2246C>T	p.Ala749Val	missense	Exon 18 of 23	NP_001278831.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	ENST00000294304.12	TSL:1 MANE Select	c.3989C>T	p.Ala1330Val	missense	Exon 18 of 23	ENSP00000294304.6
	LRP5	ENST00000529993.5	TSL:1	n.*2595C>T		non_coding_transcript_exon	Exon 18 of 23	ENSP00000436652.1
	LRP5	ENST00000529993.5	TSL:1	n.*2595C>T		3_prime_UTR	Exon 18 of 23	ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16841 AN: 152168 Hom.: 1184 Cov.: 33

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.134 AC: 32608 AN: 243164 AF XY: 0.132

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.204

Gnomad FIN exome AF: 0.0434

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.144 AC: 209942 AN: 1459492 Hom.: 16169 Cov.: 33 AF XY: 0.143 AC XY: 104076 AN XY: 726148

African (AFR) AF: 0.0373 AC: 1249 AN: 33462

American (AMR) AF: 0.181 AC: 8082 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3030 AN: 26084

East Asian (EAS) AF: 0.242 AC: 9597 AN: 39674

South Asian (SAS) AF: 0.132 AC: 11352 AN: 86212

European-Finnish (FIN) AF: 0.0457 AC: 2383 AN: 52128

Middle Eastern (MID) AF: 0.149 AC: 853 AN: 5742

European-Non Finnish (NFE) AF: 0.149 AC: 165387 AN: 1111272

Other (OTH) AF: 0.133 AC: 8009 AN: 60288

GnomAD4 genome AF: 0.111 AC: 16846 AN: 152286 Hom.: 1182 Cov.: 33 AF XY: 0.108 AC XY: 8013 AN XY: 74456

African (AFR) AF: 0.0427 AC: 1773 AN: 41568

American (AMR) AF: 0.156 AC: 2383 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3472

East Asian (EAS) AF: 0.205 AC: 1062 AN: 5178

South Asian (SAS) AF: 0.130 AC: 629 AN: 4828

European-Finnish (FIN) AF: 0.0389 AC: 413 AN: 10618

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9611 AN: 68000

Other (OTH) AF: 0.134 AC: 283 AN: 2112

Alfa AF: 0.140 Hom.: 6141

Bravo AF: 0.122

TwinsUK AF: 0.156 AC: 580

ALSPAC AF: 0.149 AC: 576

ESP6500AA AF: 0.0475 AC: 209

ESP6500EA AF: 0.141 AC: 1209

ExAC AF: 0.128 AC: 15545

Asia WGS AF: 0.140 AC: 488 AN: 3478

EpiCase AF: 0.145

EpiControl AF: 0.143

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Increased bone mineral density (1)
-	-	1	Osteogenesis imperfecta (1)
-	-	1	Osteoporosis with pseudoglioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.24	N
PhyloP100		0.48
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.22
Sift	Benign	0.21	T
Sift4G	Benign	0.30	T
Polyphen		0.015	B
Vest4		0.058
MPC		0.41
ClinPred		0.0090	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.029
gMVP		0.34
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3736228; hg19: chr11-68201295; COSMIC: COSV53725745; COSMIC: COSV53725745;