chr4-1805643-A-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000142.5(FGFR3):​c.1619A>G​(p.Asn540Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,096 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N540D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

7
9
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 8.73

Publications

38 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: Pathogenic. The variant received 16 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
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-1805642-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 4-1805643-A-G is Pathogenic according to our data. Variant chr4-1805643-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGFR3NM_000142.5 linkc.1619A>G p.Asn540Ser 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.1619A>G p.Asn540Ser missense_variant Exon 12 of 18 5 NM_000142.5 ENSP00000414914.2 P22607-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152216
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000399
AC:
1
AN:
250598
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.000164
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1460880
Hom.:
0
Cov.:
34
AF XY:
0.0000193
AC XY:
14
AN XY:
726800
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33462
American (AMR)
AF:
0.00
AC:
0
AN:
44698
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26108
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39688
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.0000379
AC:
2
AN:
52818
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000117
AC:
13
AN:
1111724
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60358
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
3
5
8
10
13
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:
0.0000197
AC:
3
AN:
152216
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
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:
0.0000294
AC:
2
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
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:
0.0000226
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypochondroplasia Pathogenic:4
May 15, 2003
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Feb 01, 2024
Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 08, 2025
Clinical Biomedical Laboratory, Shriners Hospital For Children - Canada
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is predicted to substitute an asparagine residue by a serine residue. This variant is rare in the general population (Genome Aggregation Database v2.1.1). This variant has been reported multiple times in the literature as a cause of hypochondroplasia (PMID 10777366, 25614871).Based on the ACMG variant interpretation guidelines, the available evidence supports classification of this variant as pathogenic. -

Jun 01, 2023
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016349 /PMID: 10777366 /3billion dataset). Different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Lys, p.Asn540Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016337, VCV000016338, VCV000016344, VCV000374828, VCV001325830 /PMID: 7670477, 8589686, 9452043 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:4
Aug 01, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 14, 2022
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29542187, 10777366, 23045425, 15909185, 12707965) -

Mar 28, 2018
Clinical Genetics and Genomics, Karolinska University Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 540 of the FGFR3 protein (p.Asn540Ser). This variant is present in population databases (rs77722678, gnomAD no frequency). This missense change has been observed in individuals with FGFR3-related disorders (PMID: 10777366, 12707965, 23045425). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16349). Invitae Evidence 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 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. This variant disrupts the p.Asn540 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11055896, 23165795, 25614871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Achondroplasia Pathogenic:2
-
Suma Genomics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 28, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: FGFR3 c.1619A>G (p.Asn540Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250598 control chromosomes. c.1619A>G has been reported in the literature in multiple families affected with Hypochondroplasia and shown to segregate with disease (deSanctis_2012, Mortier_2000, Thauvin-Robinet_2003). These data indicate that the variant is very likely to be associated with disease. Other variants at this amino acid, N540K and N540T have also been reported to associate with Hypochondroplasia in the literature. At least one publication reports experimental evidence evaluating an impact on protein function (Patani_2016). These results showed a 10 fold increase in auto-phosphorylation and a 2 fold increase in substrate phosphorylation. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and Pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

Neurodevelopmental delay Pathogenic:1
-
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Pathogenic:1
Jul 22, 2024
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1619A>G (p.N540S) alteration is located in exon 12 (coding exon 11) of the FGFR3 gene. This alteration results from a A to G substitution at nucleotide position 1619, causing the asparagine (N) at amino acid position 540 to be replaced by a serine (S). for FGFR3-related skeletal disorders; however, its clinical significance for CATSHL syndrome is uncertain. Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/250598) total alleles studied. The highest observed frequency was <0.001% (1/6112) of alleles. The p.N540S alteration has been seen in multiple probands with clinical features of hypochondroplasia and is present in similarly affected relatives in at least four families (Mortier, 2000; Thauvin-Robinet, 2003; De Sanctis, 2012; Fang, 2024; Doherty, 2007; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, p.N540S is slightly destabilizing to FGFR3 (Tyhonas, 2024). Functional analysis demonstrated that the p.N540S alteration results in a gain of function effect (Patani, 2016). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;D;.;.;.
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;D;.
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Benign
0.44
N;.;.;.;.
PhyloP100
8.7
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-4.4
D;D;D;D;D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Uncertain
0.026
D;T;D;D;D
Polyphen
1.0
D;D;D;D;D
Vest4
0.91
MutPred
0.94
Loss of sheet (P = 0.1398);.;.;.;.;
MVP
0.95
MPC
0.83
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.81
gMVP
0.63
Mutation Taster
=0/100
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: rs77722678; hg19: chr4-1807370; API