rs121913112
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000142.5(FGFR3):c.1537G>A(p.Asp513Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000409 in 1,613,026 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D513Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_000142.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR3 | NM_000142.5 | c.1537G>A | p.Asp513Asn | missense_variant, splice_region_variant | 12/18 | ENST00000440486.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.1537G>A | p.Asp513Asn | missense_variant, splice_region_variant | 12/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250540Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135688
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1460796Hom.: 0 Cov.: 34 AF XY: 0.0000427 AC XY: 31AN XY: 726704
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 12, 2019 | The FGFR3 c.1537G>A; p.Asp513Asn variant (rs121913112) is reported in the literature in a family affected with lacrimo-auriculo-dento-digital syndrome (Rohmann 2006). This variant co-segregated with disease in this family and was not observed in either parent of the oldest affected individual, suggesting a de novo origin (Rohmann 2006). This variant is found in the general population with an overall allele frequency of 0.005% (13/281908 alleles) in the Genome Aggregation Database. The aspartate at codon 513 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Asp513Asn variant is uncertain at this time. References: Rohmann E et al. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006 Apr;38(4):414-7. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 17682060, 19215249, 28483234, 16501574) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 513 of the FGFR3 protein (p.Asp513Asn). This variant is present in population databases (rs121913112, gnomAD 0.009%). This missense change has been observed in individual(s) with lacrimo-auriculo-dento-digital syndrome (PMID: 16501574). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16354). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Levy-Hollister syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2006 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2023 | Variant summary: FGFR3 c.1537G>A (p.Asp513Asn) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250540 control chromosomes. This frequency does not allow conclusions about variant significance. c.1537G>A has been reported in the literature as a reportedly de-novo variant in an affected father and two of his offspring affected with features of Lacrimo-auriculo-dento-digital (LADD) syndrome (example, Rohmann_2006 cited in Ryu_2020). To our knowledge, it has not been reported in the literature in individuals affected with Achondroplasia. These data indicate that the variant may be associated with disease although the frequency in control cohorts seems at odds with the reportedly de-novo inheritance in the family ascertained above (Rohmann_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at