11-46875946-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_002334.4(LRP4):c.3557G>C(p.Trp1186Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,072 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1186L) has been classified as Uncertain significance.
Frequency
Consequence
NM_002334.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRP4 | NM_002334.4 | c.3557G>C | p.Trp1186Ser | missense_variant | 26/38 | ENST00000378623.6 | |
LRP4 | XM_017017734.2 | c.3557G>C | p.Trp1186Ser | missense_variant | 26/39 | ||
LRP4 | XM_011520103.3 | c.2753G>C | p.Trp918Ser | missense_variant | 20/32 | ||
LRP4 | XM_011520104.3 | c.1322G>C | p.Trp441Ser | missense_variant | 11/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRP4 | ENST00000378623.6 | c.3557G>C | p.Trp1186Ser | missense_variant | 26/38 | 1 | NM_002334.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251420Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Sclerosteosis 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2015 | The W1186S variant in the LRP4 gene has been reported previously as a de novo heterozygous mutation in an individual with sclerosteosis, syndactyly, and shortening of several phalanges (Leupin et al., 2011). Functional studies demonstrated that W1186S impairs sclerostin interaction with LRP4 and sclerostin facilitator function (Leupin et al., 2011). The W1186S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W1186S variant is a non-conservative amino acid substitution which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts that this variant is probably damaging to the protein structure/function. The W1186S variant is a strong candidate for a disease-causing variant, however the possibility that it may be a rare benign variant cannot be excluded. - |
Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 11, 2018 | This sequence change replaces tryptophan with serine at codon 1186 of the LRP4 protein (p.Trp1186Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with sclerosteosis (PMID: 21471202). ClinVar contains an entry for this variant (Variation ID: 30410). Experimental studies have shown that this missense change impairs LRP4 protein function in vitro (PMID: 21471202, 24234652). 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