chr14-91936950-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_006329.4(FBLN5):c.376G>A(p.Val126Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,614,216 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006329.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBLN5 | NM_006329.4 | c.376G>A | p.Val126Met | missense_variant | Exon 4 of 11 | ENST00000342058.9 | NP_006320.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00195 AC: 297AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00183 AC: 456AN: 249058Hom.: 0 AF XY: 0.00165 AC XY: 222AN XY: 134820
GnomAD4 exome AF: 0.00300 AC: 4381AN: 1461884Hom.: 8 Cov.: 32 AF XY: 0.00293 AC XY: 2128AN XY: 727242
GnomAD4 genome AF: 0.00194 AC: 296AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.00170 AC XY: 127AN XY: 74494
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
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FBLN5: BS3:Supporting -
Identified in patients with age-related macular degeneration or spinal Charcot-Marie-Tooth, as well as in control cohorts (Lotery et al., 2006; Auer-Grumbach et al., 2011; Duvvari et al., 2016); Expression of this variant in COS-7 cells demonstrated no significant effect on fibulin-5 protein secretion or quantity compared to wild-type (Lotery et al., 2006), and biophysical techniques did not suggest any gross structural changes in association with this variant (Jones et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as either a variant of uncertain significance or a likely benign variant but additional evidence is not available (ClinVar Variant ID# 218360; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21616967, 20389311, 27007659, 21576112, 22943132, 23293578, 16652333, 20007835, 23532871) -
Charcot-Marie-Tooth disease, demyelinating, IIA 1H Pathogenic:1
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not specified Benign:1
Variant summary: FBLN5 c.376G>A (p.Val126Met) results in a conservative amino acid change located in the Growth factor receptor domain (IPR009030) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 249058 control chromosomes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBLN5 causing Cutis laxa, autosomal recessive, type 1A phenotype (0.0011). c.376G>A has been reported in the literature in individuals affected with cuticular drusen, without strong evidence for causality (Duvvari_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Cutis laxa, autosomal recessive, type 1A. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27007659). ClinVar contains an entry for this variant (Variation ID: 218360). Based on the evidence outlined above, the variant was classified as likely benign. -
Macular degeneration, age-related, 3 Benign: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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
FBLN5-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cutis laxa Benign: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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at