NM_000142.5:c.1537G>A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar 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 4 ACMG points.
Transcripts
RefSeq
Ensembl
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:4
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. -
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. -
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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) -
Lacrimoauriculodentodigital syndrome 2 Pathogenic:1
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not specified Uncertain:1
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. -
Levy-Hollister syndrome Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS. Following criteria are met: 0103 - Both gain and loss of function are known mechanisms of disease in this gene. Gain of function variants in this gene have been associated with autosomal dominant skeletal dysplasias, while loss of function variants have been have been associated with autosomal recessive CATSHL syndrome (PMID: 25614871). The disease mechanism for autosomal dominant LADD syndrome is not clearly established. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD syndrome patients, even within the same family (PMID: 16501574). 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position has been observed in gnomAD (v2) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in a placental mammal. (SB) 0600 - Variant is located in the annotated protein tyrosine kinase domain (PDB, PMID: 16501574). (I) 0710 - Another missense variants comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a tyrosine has also been reported as a variant of uncertain significance in a VCGS patient. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in a patient with LADD syndrome and segregated in his two affected children (ClinVar, PMID: 16501574). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited by trio analysis (20W000787). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at