rs387906883
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate
The NM_002334.4(LRP4):c.3557G>T(p.Trp1186Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. W1186S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002334.4 missense
Scores
Clinical Significance
Conservation
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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.3557G>T | p.Trp1186Leu | missense_variant | 26/38 | ENST00000378623.6 | |
LRP4 | XM_017017734.2 | c.3557G>T | p.Trp1186Leu | missense_variant | 26/39 | ||
LRP4 | XM_011520103.3 | c.2753G>T | p.Trp918Leu | missense_variant | 20/32 | ||
LRP4 | XM_011520104.3 | c.1322G>T | p.Trp441Leu | missense_variant | 11/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP4 | ENST00000378623.6 | c.3557G>T | p.Trp1186Leu | missense_variant | 26/38 | 1 | NM_002334.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251420Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7AN XY: 727244
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74346
ClinVar
Submissions by phenotype
Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with LRP4-related conditions. This variant is present in population databases (rs387906883, gnomAD 0.003%). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 1186 of the LRP4 protein (p.Trp1186Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at