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rs4647924

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000142.5(FGFR3):c.749C>A(p.Pro250Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,606,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P250L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

10
8
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.85
Variant links:
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 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000142.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-1801844-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FGFR3NM_000142.5 linkuse as main transcriptc.749C>A p.Pro250Gln missense_variant 7/18 ENST00000440486.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FGFR3ENST00000440486.8 linkuse as main transcriptc.749C>A p.Pro250Gln missense_variant 7/185 NM_000142.5 P4P22607-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152186
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1454806
Hom.:
0
Cov.:
39
AF XY:
0.00
AC XY:
0
AN XY:
722914
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152186
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.040
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.89
D;T;.;.;T;.;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;.;D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Uncertain
2.0
M;.;M;M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D;N;N
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-6.1
D;D;D;D;.;D;D
REVEL
Pathogenic
0.73
Sift
Pathogenic
0.0
D;D;D;D;.;D;D
Sift4G
Uncertain
0.017
D;D;D;D;D;D;D
Polyphen
1.0
D;D;P;D;.;D;.
Vest4
0.69
MutPred
0.68
Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);Loss of glycosylation at P250 (P = 0.0271);.;
MVP
0.97
MPC
0.75
ClinPred
1.0
D
GERP RS
3.1
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
2.1
Varity_R
0.91
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4647924; hg19: chr4-1803571; COSMIC: COSV53402284; COSMIC: COSV53402284; API