rs80358310
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PP2PP3_Strong
The NM_002335.4(LRP5):c.1604C>T(p.Thr535Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. T535T) has been classified as Likely benign.
Frequency
Consequence
NM_002335.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP5 | NM_002335.4 | c.1604C>T | p.Thr535Met | missense_variant | 8/23 | ENST00000294304.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.1604C>T | p.Thr535Met | missense_variant | 8/23 | 1 | NM_002335.4 | P1 | |
LRP5 | ENST00000529993.5 | c.*16C>T | 3_prime_UTR_variant, NMD_transcript_variant | 7/23 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251396Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135894
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461810Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727216
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 12, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LRP5 protein function. This missense change has been observed in individual(s) with familial exudative vitreoretinopathy (PMID: 15981244). This variant is present in population databases (rs80358310, gnomAD 0.002%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 535 of the LRP5 protein (p.Thr535Met). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at