rs1127291

Variant names:

• chr11-68446521-C-T
• rs1127291
• NM_002335.4:c.4574C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-68446521-C-T
• chr11-68446521-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002335.4(LRP5):​c.4574C>T​(p.Ala1525Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,754 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. A1525A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0096 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (110 hom.)
• Consequence: LRP5 NM_002335.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.511
• Publications: 20 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 -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 autosomal dominant osteopetrosis 1, osteoporosis-pseudoglioma syndrome, bone mineral density quantitative trait locus 1, autosomal dominant osteosclerosis, Worth type, polycystic liver disease 4 with or without kidney cysts, hyperostosis corticalis generalisata, osteosclerosis-developmental delay-craniosynostosis syndrome, exudative vitreoretinopathy 4, polycystic liver disease 1, exudative vitreoretinopathy, LRP5-related exudative vitreoretinopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0074311197).
• BP6: Variant 11-68446521-C-T is Benign according to our data. Variant chr11-68446521-C-T is described in ClinVar as Benign. ClinVar VariationId is 195672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00958 (1460/152332) while in subpopulation NFE AF = 0.0112 (764/68020). AF 95% confidence interval is 0.0106. There are 11 homozygotes in GnomAd4. There are 656 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR,Unknown,SD gene

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.4574C>T	p.Ala1525Val	missense	Exon 22 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.2831C>T	p.Ala944Val	missense	Exon 22 of 23	NP_001278831.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	ENST00000294304.12	TSL:1 MANE Select	c.4574C>T	p.Ala1525Val	missense	Exon 22 of 23	ENSP00000294304.6	O75197
	LRP5	ENST00000529993.5	TSL:1	n.*3180C>T		non_coding_transcript_exon	Exon 22 of 23	ENSP00000436652.1	E9PHY1
	LRP5	ENST00000529993.5	TSL:1	n.*3180C>T		3_prime_UTR	Exon 22 of 23	ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes AF: 0.00959 AC: 1460 AN: 152214 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.00770 AC: 1934 AN: 251260 AF XY: 0.00746

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.00794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00533

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.0107 AC: 15642 AN: 1461422 Hom.: 110 Cov.: 31 AF XY: 0.0103 AC XY: 7482 AN XY: 727050

African (AFR) AF: 0.00959 AC: 321 AN: 33478

American (AMR) AF: 0.00537 AC: 240 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00765 AC: 200 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86252

European-Finnish (FIN) AF: 0.00613 AC: 327 AN: 53334

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.0125 AC: 13939 AN: 1111656

Other (OTH) AF: 0.00947 AC: 572 AN: 60382

GnomAD4 genome AF: 0.00958 AC: 1460 AN: 152332 Hom.: 11 Cov.: 32 AF XY: 0.00881 AC XY: 656 AN XY: 74480

African (AFR) AF: 0.0105 AC: 435 AN: 41588

American (AMR) AF: 0.0100 AC: 153 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00489 AC: 52 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 764 AN: 68020

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.0105 Hom.: 31

Bravo AF: 0.00986

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00864 AC: 38

ESP6500EA AF: 0.00978 AC: 84

ExAC AF: 0.00787 AC: 956

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0114

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	3	not specified (3)
-	-	1	Osteogenesis imperfecta (1)
-	-	1	Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 1;C1851402:Exudative vitreoretinopathy 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.51
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.16
Sift	Benign	0.43	T
Sift4G	Benign	0.50	T
Polyphen		0.0060	B
Vest4		0.12
MVP		0.53
MPC		0.41
ClinPred		0.013	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.22
Mutation Taster		=98/2	disease causing (ClinVar)

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: rs1127291; hg19: chr11-68213989; COSMIC: COSV99037169; COSMIC: COSV99037169;