chr4-1802011-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000142.5(FGFR3):​c.916G>A​(p.Val306Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,459,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V306V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.66

Publications

8 publications found
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]
FGFR3 Gene-Disease associations (from GenCC):
  • achondroplasia
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • Crouzon syndrome-acanthosis nigricans syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
  • hypochondroplasia
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
  • lacrimoauriculodentodigital syndrome 2
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • Muenke syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
  • thanatophoric dysplasia type 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, ClinGen
  • thanatophoric dysplasia type 2
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
  • camptodactyly-tall stature-scoliosis-hearing loss syndrome
    Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
  • severe achondroplasia-developmental delay-acanthosis nigricans syndrome
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
  • isolated brachycephaly
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • isolated plagiocephaly
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • LADD syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • LADD syndrome 1
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a domain Ig-like C2-type 3 (size 102) in uniprot entity FGFR3_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_000142.5

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGFR3NM_000142.5 linkc.916G>A p.Val306Ile missense_variant Exon 7 of 18 ENST00000440486.8 NP_000133.1 P22607-1Q0IJ44

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGFR3ENST00000440486.8 linkc.916G>A p.Val306Ile missense_variant Exon 7 of 18 5 NM_000142.5 ENSP00000414914.2 P22607-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD2 exomes
AF:
0.0000448
AC:
11
AN:
245456
AF XY:
0.0000149
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000292
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1459794
Hom.:
0
Cov.:
37
AF XY:
0.00000551
AC XY:
4
AN XY:
726198
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33444
American (AMR)
AF:
0.000224
AC:
10
AN:
44664
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26098
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39666
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86176
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52046
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111622
Other (OTH)
AF:
0.00
AC:
0
AN:
60310
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.455
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.0000497
AC:
6
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 582777). This variant has not been reported in the literature in individuals affected with FGFR3-related conditions. This variant is present in population databases (rs774047997, gnomAD 0.03%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 306 of the FGFR3 protein (p.Val306Ile). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
T;T;.;.;T;.
Eigen
Benign
0.11
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;.
M_CAP
Pathogenic
0.49
D
MetaRNN
Uncertain
0.47
T;T;T;T;T;T
MetaSVM
Uncertain
0.79
D
MutationAssessor
Benign
0.15
N;.;N;N;.;N
PhyloP100
9.7
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.44
N;N;N;N;.;N
REVEL
Uncertain
0.47
Sift
Benign
0.058
T;T;T;T;.;T
Sift4G
Benign
0.20
T;T;T;T;D;T
Polyphen
0.90
P;B;B;D;.;D
Vest4
0.68
MutPred
0.32
Loss of catalytic residue at V306 (P = 0.0292);Loss of catalytic residue at V306 (P = 0.0292);Loss of catalytic residue at V306 (P = 0.0292);Loss of catalytic residue at V306 (P = 0.0292);Loss of catalytic residue at V306 (P = 0.0292);Loss of catalytic residue at V306 (P = 0.0292);
MVP
0.90
MPC
0.45
ClinPred
0.19
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.23
gMVP
0.36
Mutation Taster
=46/54
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs774047997; hg19: chr4-1803738; COSMIC: COSV53417648; COSMIC: COSV53417648; API