rs727505371
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP3PP5
The NM_023110.3(FGFR1):c.1037_1038del(p.Ser346TyrfsTer61) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FGFR1
NM_023110.3 frameshift
NM_023110.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists 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 both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 8-38421839-TAG-T is Pathogenic according to our data. Variant chr8-38421839-TAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180154.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1}. Variant chr8-38421839-TAG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR1 | NM_023110.3 | c.1037_1038del | p.Ser346TyrfsTer61 | frameshift_variant | 8/18 | ENST00000447712.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR1 | ENST00000447712.7 | c.1037_1038del | p.Ser346TyrfsTer61 | frameshift_variant | 8/18 | 1 | NM_023110.3 | P4 | |
ENST00000528407.1 | upstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249924Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135550
GnomAD3 exomes
AF:
AC:
1
AN:
249924
Hom.:
AF XY:
AC XY:
1
AN XY:
135550
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 exome
AF:
AC:
1
AN:
1461886
Hom.:
AF XY:
AC XY:
1
AN XY:
727244
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | case-control | Chan Lab, Boston Children's Hospital | Nov 01, 2014 | - - |
Delayed puberty Pathogenic:1
Likely pathogenic, criteria provided, single submitter | case-control | Chan Lab, Boston Children's Hospital | Nov 01, 2014 | - - |
Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 180154). This premature translational stop signal has been observed in individual(s) with Kallman syndrome (PMID: 23533228). This variant is present in population databases (rs727505371, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser346Tyrfs*61) 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). - |
Hypogonadotropic hypogonadism 2 with or without anosmia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Reproductive Endocrine Unit, Massachusetts General Hospital | May 04, 2023 | The variant NM_023110.2:c.1037_1038del, p.(Ser346Tyrfs*61) het has been classified as VUS based on the variant meeting the following ACMG Criteria: PVS1,PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 9
Find out detailed SpliceAI scores and Pangolin per-transcript scores at