11-68312730-C-A

Variant summary

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

The NM_002335.4(LRP5):c.16C>A(p.Pro6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,052,528 control chromosomes in the GnomAD database, including 14 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (9 hom.)
• Consequence: LRP5 NM_002335.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.171

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP5
• BP4: Computational evidence support a benign effect (MetaRNN=0.010892689).
• BP6: Variant 11-68312730-C-A is Benign according to our data. Variant chr11-68312730-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 499142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00292 (424/145040) while in subpopulation AMR AF= 0.0263 (387/14732). AF 95% confidence interval is 0.0241. There are 5 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.16C>A	p.Pro6Thr	missense_variant	1/23	ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.16C>A	p.Pro6Thr	missense_variant	1/23	1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.16C>A	p.Pro6Thr	missense_variant, NMD_transcript_variant	1/23	1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 425 AN: 144936 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000401

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000138

Gnomad OTH AF: 0.00349

GnomAD3 exomes AF: 0.00872 AC: 125 AN: 14342 Hom.: 5 AF XY: 0.00634 AC XY: 55 AN XY: 8672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0462

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00870

GnomAD4 exome AF: 0.000301 AC: 273 AN: 907488 Hom.: 9 Cov.: 28 AF XY: 0.000259 AC XY: 112 AN XY: 432226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0371

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000380

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000631

Gnomad4 OTH exome AF: 0.000749

GnomAD4 genome AF: 0.00292 AC: 424 AN: 145040 Hom.: 5 Cov.: 31 AF XY: 0.00320 AC XY: 226 AN XY: 70618

Gnomad4 AFR AF: 0.000447

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000403

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000138

Gnomad4 OTH AF: 0.00345

Alfa AF: 0.00228 Hom.: 3

Bravo AF: 0.00543

ExAC AF: 0.000209 AC: 3

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Osteogenesis imperfecta Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2022

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	16
Dann	Benign	0.73
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.23
MVP		0.47
MPC		0.46
ClinPred		0.029	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.089
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs771718186; hg19: chr11-68080198;