rs147259655
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_002334.4(LRP4):c.2746C>T(p.Arg916Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,802 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R916H) has been classified as Uncertain significance.
Frequency
Consequence
NM_002334.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP4 | NM_002334.4 | c.2746C>T | p.Arg916Cys | missense_variant | 20/38 | ENST00000378623.6 | |
LRP4 | XM_017017734.2 | c.2746C>T | p.Arg916Cys | missense_variant | 20/39 | ||
LRP4 | XM_011520103.3 | c.1942C>T | p.Arg648Cys | missense_variant | 14/32 | ||
LRP4 | XM_011520104.3 | c.511C>T | p.Arg171Cys | missense_variant | 5/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP4 | ENST00000378623.6 | c.2746C>T | p.Arg916Cys | missense_variant | 20/38 | 1 | NM_002334.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251468Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135904
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461656Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727088
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 08, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 916 of the LRP4 protein (p.Arg916Cys). This variant is present in population databases (rs147259655, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with LRP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 535801). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LRP4 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at