rs80358317
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 5P and 8B. PM1PM2PP2BP4_StrongBS1
The NM_002335.4(LRP5):āc.3361A>Gā(p.Asn1121Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,612,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002335.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.3361A>G | p.Asn1121Asp | missense_variant | Exon 15 of 23 | 1 | NM_002335.4 | ENSP00000294304.6 | ||
LRP5 | ENST00000529993.5 | n.*1967A>G | non_coding_transcript_exon_variant | Exon 15 of 23 | 1 | ENSP00000436652.1 | ||||
LRP5 | ENST00000529993.5 | n.*1967A>G | 3_prime_UTR_variant | Exon 15 of 23 | 1 | ENSP00000436652.1 |
Frequencies
GnomAD3 genomes AF: 0.000395 AC: 60AN: 152046Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000640 AC: 160AN: 250134Hom.: 0 AF XY: 0.000620 AC XY: 84AN XY: 135420
GnomAD4 exome AF: 0.000202 AC: 295AN: 1460534Hom.: 0 Cov.: 35 AF XY: 0.000202 AC XY: 147AN XY: 726682
GnomAD4 genome AF: 0.000394 AC: 60AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34AN XY: 74400
ClinVar
Submissions by phenotype
Exudative vitreoretinopathy 4 Uncertain:2
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This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Exudative vitreoretinopathy 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1-Supporting => BS1 downgraded in strength to supporting. -
not provided Benign:2
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Reported previously in individuals with familial exudative vitreoretinopathy, but some individuals were reported to have causative variants in other genes and the variant was inherited from an unaffected parent in multiple families (Qin et al., 2005; Yang et al., 2012; Seo et al., 2015; Tang et al., 2017; Li et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26244290, 29181528, 28251098, 23077402, 15981244, 30452590, 31169861, 30097784) -
Osteogenesis imperfecta Uncertain:1
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Osteoporosis with pseudoglioma;C0432273:Worth disease;C1843330:Autosomal dominant osteopetrosis 1;C1866079:Bone mineral density quantitative trait locus 1;C1866176:Exudative vitreoretinopathy 4;C4693479:Polycystic liver disease 4 with or without kidney cysts Uncertain:1
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LRP5-related disorder Uncertain:1
The LRP5 c.3361A>G variant is predicted to result in the amino acid substitution p.Asn1121Asp. This variant has been reported in individuals with familial exudative vitreoretinopathy; however, it has also been detected in unaffected parents and in individuals in whom another causative variant was identified (see, for example, Qin et al. 2005. PubMed ID: 15981244; Li et al. 2018. PubMed ID: 30452590; Kondo et al. 2024. PubMed ID: 38881609). This variant is reported in 0.79% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at