chr11-68312707-C-T

Variant names:

• chr11-68312707-C-T
• rs886042984
• NM_002335.4:c.-8C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002335.4(LRP5):​c.-8C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRP5 NM_002335.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.824
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

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.-8C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_002326.2	O75197
	LRP5	NM_002335.4	MANE Select	c.-8C>T		5_prime_UTR	Exon 1 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.-1773C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-8C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	ENSP00000294304.6	O75197
	LRP5	ENST00000294304.12	TSL:1 MANE Select	c.-8C>T		5_prime_UTR	Exon 1 of 23	ENSP00000294304.6	O75197
	LRP5	ENST00000529993.5	TSL:1	n.-8C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 3314 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 871938 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 409176

African (AFR) AF: 0.00 AC: 0 AN: 16404

American (AMR) AF: 0.00 AC: 0 AN: 2472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6092

East Asian (EAS) AF: 0.00 AC: 0 AN: 4852

South Asian (SAS) AF: 0.00 AC: 0 AN: 20606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1788

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 787094

Other (OTH) AF: 0.00 AC: 0 AN: 29210

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.93
PhyloP100		-0.82
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs886042984; hg19: chr11-68080175;