14-91877621-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_006329.4(FBLN5):c.1051C>T(p.Arg351Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000812 in 1,613,952 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 (★★).
Frequency
Consequence
NM_006329.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBLN5 | NM_006329.4 | c.1051C>T | p.Arg351Trp | missense_variant | Exon 10 of 11 | ENST00000342058.9 | NP_006320.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251396Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135860
GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50AN XY: 727204
GnomAD4 genome AF: 0.000112 AC: 17AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74340
ClinVar
Submissions by phenotype
Macular degeneration, age-related, 3 Pathogenic:1Uncertain:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
- -
- -
not provided Uncertain:2
Identified in a patient with age-related macular degeneration in the published literature (Stone et al., 2004) Functional data suggests that R351W indicates increased self-association of the dimers (Jones et al., 2010), though additional studies are need to elucidate the pathogenicity of R351W In silico analysis supports that this missense variant has a deleterious effect on protein structure/function Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 5481; Landrum et al., 2016) This variant is associated with the following publications: (PMID: 20007835, 15269314, 21576112) -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 351 of the FBLN5 protein (p.Arg351Trp). This variant is present in population databases (rs28939073, gnomAD 0.03%). This missense change has been observed in individual(s) with age-related macular degeneration (PMID: 15269314). ClinVar contains an entry for this variant (Variation ID: 5481). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FBLN5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect FBLN5 function (PMID: 16652333). 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. -
not specified Uncertain:1
Variant summary: FBLN5 c.1051C>T (p.Arg351Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251396 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FBLN5 causing FBLN5-Related Disorders, allowing no conclusion about variant significance. c.1051C>T has been reported in the literature in individuals affected with FBLN5-Related Disorders (Stone_2004, Wasowska_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Jones_2010, Lotery_2007). The following publications have been ascertained in the context of this evaluation (PMID: 20007835, 16652333, 15269314, 37761846). ClinVar contains an entry for this variant (Variation ID: 5481). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
See cases Uncertain:1
ACMG classification criteria: PM2, PP3 -
Age-related macular degeneration Uncertain:1
- -
Cutis laxa Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Macular degeneration, age-related, 3;C3280794:Cutis laxa, autosomal dominant 2;C5676926:Charcot-Marie-Tooth disease, demyelinating, IIA 1H;C5848058:Cutis laxa, autosomal recessive, type 1A Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at