NM_002335.4:c.518C>T

Variant names:

• chr11-68357679-C-T
• rs80358306
• NM_002335.4:c.518C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PP2 PP3 BP6 BS1

The NM_002335.4(LRP5):​c.518C>T​(p.Thr173Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T173T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00053 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: LRP5 NM_002335.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.110
• Publications: 9 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_002335.4
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748
• BP6: Variant 11-68357679-C-T is Benign according to our data. Variant chr11-68357679-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 669010.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000525 (80/152346) while in subpopulation EAS AF = 0.0027 (14/5182). AF 95% confidence interval is 0.00163. There are 1 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.518C>T	p.Thr173Met	missense	Exon 3 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.-1248C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 23	NP_001278831.1
	LRP5	NM_001291902.2		c.-1248C>T		5_prime_UTR	Exon 3 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.518C>T	p.Thr173Met	missense	Exon 3 of 23	ENSP00000294304.6	O75197
	LRP5	ENST00000529993.5	TSL:1	n.518C>T		non_coding_transcript_exon	Exon 3 of 23	ENSP00000436652.1	E9PHY1
	LRP5	ENST00000909991.1		c.518C>T	p.Thr173Met	missense	Exon 3 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000391 AC: 98 AN: 250806 AF XY: 0.000324

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000225 AC: 329 AN: 1461754 Hom.: 0 Cov.: 32 AF XY: 0.000224 AC XY: 163 AN XY: 727148

African (AFR) AF: 0.000388 AC: 13 AN: 33478

American (AMR) AF: 0.000425 AC: 19 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26130

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39696

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86220

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000159 AC: 177 AN: 1111962

Other (OTH) AF: 0.000464 AC: 28 AN: 60388

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74494

African (AFR) AF: 0.000842 AC: 35 AN: 41578

American (AMR) AF: 0.000327 AC: 5 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000450

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000371 AC: 45

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	LRP5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.92	L
PhyloP100		-0.11
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.61
Sift	Benign	0.11	T
Sift4G	Benign	0.23	T
Polyphen		0.98	D
Vest4		0.71
MVP		0.83
MPC		0.54
ClinPred		0.013	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.46
Mutation Taster		=30/70	disease causing

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: rs80358306; hg19: chr11-68125147;