NM_000142.5:c.1612A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3PP5

The NM_000142.5(FGFR3):​c.1612A>G​(p.Ile538Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I538I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

6
6
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: 6.95

Publications

31 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 4 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000142.5
PP3
MetaRNN computational evidence supports a deleterious effect, 0.784
PP5
Variant 4-1805636-A-G is Pathogenic according to our data. Variant chr4-1805636-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16345.We mark this variant Pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGFR3NM_000142.5 linkc.1612A>G p.Ile538Val missense_variant Exon 12 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.1612A>G p.Ile538Val missense_variant Exon 12 of 18 5 NM_000142.5 ENSP00000414914.2 P22607-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
34
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:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
250784
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1460960
Hom.:
0
Cov.:
34
AF XY:
0.0000110
AC XY:
8
AN XY:
726850
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33462
American (AMR)
AF:
0.0000224
AC:
1
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26106
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.0000189
AC:
1
AN:
52866
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000216
AC:
24
AN:
1111746
Other (OTH)
AF:
0.00
AC:
0
AN:
60362
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
2
3
5
6
8
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
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74362
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41448
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypochondroplasia Pathogenic:5
Jan 01, 1998
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Feb 24, 2022
MGZ Medical Genetics Center
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The heterozygous missense variant, c.1612A>G (p.Ile538Val) in FGFR3 (rs80053154) was identified in a patient diagnosed with hypochondroplasia (HCH) and hypophosphatasia (HPP). This mutation has been previously reported in a Swedish family with typical HCH (Grigelioniene et al., 1998). Her mother who had short stature and disproportionately short arms and legs also harbored this mutation. She was also identified with the compound heterozygous variants, c.1460C>T (p.Ala487Val) and c.1479C>A (p.Asn493Lys), in ALPL gene (Porntaveetus et al., 2017). -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PM2_Supporting+PP3+PS4_Supporting+PP1+PM6+PP4 -

May 31, 2019
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

not provided Pathogenic:2Uncertain:1
May 24, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10215410, 34006472, 34662886, 29758562, 29739731, 30753492, 35627109, 28763161) -

Feb 24, 2015
Clinical Genetics and Genomics, Karolinska University Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 538 of the FGFR3 protein (p.Ile538Val). This variant is present in population databases (rs80053154, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of FGFR3-related conditions and/or clinical features of hypochondroplasia (PMID: 10215410, 28763161, 30753492; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16345). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 26992226). For these reasons, this variant has been classified as Pathogenic. -

Muenke syndrome Pathogenic:1
Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

PS3,PP1,PS4,PM6 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
23
DANN
Benign
0.93
DEOGEN2
Uncertain
0.63
D;T;.;.;.
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.087
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.69
T;T;T;T;.
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Benign
0.15
N;.;.;.;.
PhyloP100
6.9
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.89
N;N;N;N;N
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0050
D;D;D;D;D
Sift4G
Uncertain
0.032
D;T;D;T;T
Polyphen
0.99
D;D;B;P;P
Vest4
0.41
MutPred
0.90
Gain of MoRF binding (P = 0.1238);.;.;.;.;
MVP
0.89
MPC
0.24
ClinPred
0.33
T
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.55
gMVP
0.55
Mutation Taster
=13/87
disease causing (ClinVar)

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: rs80053154; hg19: chr4-1807363; API