4-1807262-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000142.5(FGFR3):c.2421A>G(p.Ter807TrpextTer101) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
FGFR3
NM_000142.5 stop_lost
NM_000142.5 stop_lost
Scores
3
4
7
Clinical Significance
Conservation
PhyloP100: 3.42
Genes affected
FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-1807262-A-G is Pathogenic according to our data. Variant chr4-1807262-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2517467).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR3 | NM_000142.5 | c.2421A>G | p.Ter807TrpextTer101 | stop_lost | 18/18 | ENST00000440486.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.2421A>G | p.Ter807TrpextTer101 | stop_lost | 18/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 07, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2023 | Variant resulting in loss of the termination codon leading to protein extension by 101 amino acids; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10425034, 25728633, 25614871, 19215249, 17509076, 17320202, 34358384) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2023 | This sequence change disrupts the translational stop signal of the FGFR3 mRNA. It is expected to extend the length of the FGFR3 protein by 101 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individuals with thanatophoric dysplasia type I (PMID: 10425034, 25614871). This variant is also known as p.X807Trp. ClinVar contains an entry for this variant (Variation ID: 65564). This variant results in an extension of the FGFR3 protein. Other variant(s) that result in a similarly extended protein product (p.*807Leuext*101) have been determined to be pathogenic (PMID: 10425034, 25728633; Invitae). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Thanatophoric dysplasia type 1 Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Apr 05, 2019 | This FGFR3 variant is absent from large population datasets and has been identified in individuals with thanatophoric dysplasia type I (TD I). c.2421A>G (p.Ter807Trp) results in the elimination of a termination codon and subsequent protein elongation. The 141 amino acid residues resulting from the elimination for the termination codon contain a highly hydrophobic domain that is rich in cysteine, which is consistent with the known molecular mechanism for TD type I. We consider this variant pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N;N;N
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Polyphen
B
Vest4
MutPred
Loss of methylation at K785 (P = 0.0069);
MVP
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at