rs121909633

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1PM2PM5PP2BP4_Moderate

The NM_023110.3(FGFR1):​c.899T>G​(p.Ile300Ser) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I300T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

FGFR1
NM_023110.3 missense

Scores

5
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.639
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain Ig-like C2-type 3 (size 102) in uniprot entity FGFR1_HUMAN there are 42 pathogenic changes around while only 1 benign (98%) in NM_023110.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-38424546-A-G is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR1. . Gene score misZ 2.4852 (greater than the threshold 3.09). Trascript score misZ 4.2642 (greater than threshold 3.09). GenCC has associacion of gene with hypogonadotropic hypogonadism 2 with or without anosmia, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism, tooth agenesis, isolated trigonocephaly, Pfeiffer syndrome type 1, Jackson-Weiss syndrome, Pfeiffer syndrome, Kallmann syndrome, septooptic dysplasia, hypogonadotropic hypogonadism 7 with or without anosmia, holoprosencephaly, osteoglophonic dwarfism, Hartsfield-Bixler-Demyer syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.17622468).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FGFR1NM_023110.3 linkuse as main transcriptc.899T>G p.Ile300Ser missense_variant 7/18 ENST00000447712.7 NP_075598.2 P11362-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FGFR1ENST00000447712.7 linkuse as main transcriptc.899T>G p.Ile300Ser missense_variant 7/181 NM_023110.3 ENSP00000400162.2 P11362-1
FGFR1ENST00000397091.9 linkuse as main transcriptc.893T>G p.Ile298Ser missense_variant 7/181 ENSP00000380280.5 P11362-7
FGFR1ENST00000397108.8 linkuse as main transcriptc.893T>G p.Ile298Ser missense_variant 8/191 ENSP00000380297.4 P11362-7
FGFR1ENST00000397113.6 linkuse as main transcriptc.893T>G p.Ile298Ser missense_variant 7/182 ENSP00000380302.2 P11362-7
FGFR1ENST00000356207.9 linkuse as main transcriptc.632T>G p.Ile211Ser missense_variant 6/171 ENSP00000348537.5 P11362-3
FGFR1ENST00000397103.5 linkuse as main transcriptc.626T>G p.Ile209Ser missense_variant 5/165 ENSP00000380292.1 E7EU09
FGFR1ENST00000326324.10 linkuse as main transcriptc.626T>G p.Ile209Ser missense_variant 6/171 ENSP00000327229.6 P11362-14
FGFR1ENST00000487647.5 linkuse as main transcriptn.*590T>G non_coding_transcript_exon_variant 6/121 ENSP00000435254.1 E9PKX3
FGFR1ENST00000487647.5 linkuse as main transcriptn.*590T>G 3_prime_UTR_variant 6/121 ENSP00000435254.1 E9PKX3

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.61
.;.;D;T;.;.;.;.;.;.;T;.
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.015
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.84
T;.;T;D;T;T;.;T;T;T;T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.18
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
1.4
.;.;L;.;.;L;.;.;.;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.7
N;N;N;.;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.060
T;T;T;.;D;T;T;T;T;T;T;T
Sift4G
Benign
0.27
T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.13
B;B;B;B;.;B;B;B;B;B;.;B
Vest4
0.28
MutPred
0.58
.;.;Gain of disorder (P = 0.0037);.;.;Gain of disorder (P = 0.0037);.;.;.;.;.;.;
MVP
0.88
MPC
1.9
ClinPred
0.39
T
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.28
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-38282064; API