GeneBe

rs1554552774

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_023110.3(FGFR1):​c.1430+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

FGFR1
NM_023110.3 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.60

Publications

1 publications found
Variant links:
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]
FGFR1 Gene-Disease associations (from GenCC):
  • encephalocraniocutaneous lipomatosis
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • Hartsfield-Bixler-Demyer syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
  • hypogonadotropic hypogonadism 2 with or without anosmia
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • osteoglophonic dysplasia
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • Pfeiffer syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • Pfeiffer syndrome type 1
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • Jackson-Weiss syndrome
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • hypogonadotropic hypogonadism
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • isolated trigonocephaly
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Kallmann syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • septooptic dysplasia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • tooth agenesis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • holoprosencephaly
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-38418227-C-A is Pathogenic according to our data. Variant chr8-38418227-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 974812.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGFR1NM_023110.3 linkc.1430+1G>T splice_donor_variant, intron_variant Intron 10 of 17 ENST00000447712.7 NP_075598.2 P11362-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGFR1ENST00000447712.7 linkc.1430+1G>T splice_donor_variant, intron_variant Intron 10 of 17 1 NM_023110.3 ENSP00000400162.2 P11362-1
FGFR1ENST00000397091.9 linkc.1424+1G>T splice_donor_variant, intron_variant Intron 10 of 17 1 ENSP00000380280.5 P11362-7
FGFR1ENST00000397108.8 linkc.1424+1G>T splice_donor_variant, intron_variant Intron 11 of 18 1 ENSP00000380297.4 P11362-7
FGFR1ENST00000397113.6 linkc.1424+1G>T splice_donor_variant, intron_variant Intron 10 of 17 2 ENSP00000380302.2 P11362-7
FGFR1ENST00000356207.9 linkc.1163+1G>T splice_donor_variant, intron_variant Intron 9 of 16 1 ENSP00000348537.5 P11362-3
FGFR1ENST00000397103.5 linkc.1163+1G>T splice_donor_variant, intron_variant Intron 8 of 15 5 ENSP00000380292.1 E7EU09
FGFR1ENST00000326324.10 linkc.1157+1G>T splice_donor_variant, intron_variant Intron 9 of 16 1 ENSP00000327229.6 P11362-14
FGFR1ENST00000487647.5 linkn.*1121+1G>T splice_donor_variant, intron_variant Intron 9 of 11 1 ENSP00000435254.1 E9PKX3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1
-
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
PhyloP100
7.6
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DL_spliceai
1.0
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1554552774; hg19: chr8-38275745; API