rs121909639
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_023110.3(FGFR1):c.1825C>T(p.Arg609Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,606 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R609R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_023110.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR1 | NM_023110.3 | c.1825C>T | p.Arg609Ter | stop_gained | 13/18 | ENST00000447712.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR1 | ENST00000447712.7 | c.1825C>T | p.Arg609Ter | stop_gained | 13/18 | 1 | NM_023110.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461606Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727122
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Reproductive Endocrine Unit, Massachusetts General Hospital | May 04, 2023 | The variant NM_023110.2:c.1825C>T, p.(Arg609*) het has been classified as P1c based on the variant meeting the following ACMG Criteria: PVS1,PM2,PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 28, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2015 | The R609X nonsense variant in the FGFR1 gene has been reported previously inassociation with Kallmann syndrome (Riley et al., 2007; Marcos et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. Therefore, we consider the R609X variant to be pathogenic. - |
Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 27, 2023 | This sequence change creates a premature translational stop signal (p.Arg609*) in the FGFR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FGFR1 are known to be pathogenic (PMID: 12627230). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Kallmann syndrome (PMID: 17360555). ClinVar contains an entry for this variant (Variation ID: 16296). For these reasons, this variant has been classified as Pathogenic. - |
Hypogonadotropic hypogonadism 2 with anosmia Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Mar 13, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at