chr4-1801844-C-T

Variant names:

• chr4-1801844-C-T
• rs4647924
• NM_000142.5:c.749C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_000142.5(FGFR3):​c.749C>T​(p.Pro250Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,606,994 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P250Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 5.85
• Publications: 178 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000142.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-1801844-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 4-1801844-C-T is Pathogenic according to our data. Variant chr4-1801844-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533893.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000142.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	NM_000142.5	MANE Select	c.749C>T	p.Pro250Leu	missense	Exon 7 of 18	NP_000133.1
	FGFR3	NM_001163213.2		c.749C>T	p.Pro250Leu	missense	Exon 7 of 18	NP_001156685.1
	FGFR3	NM_001354809.2		c.749C>T	p.Pro250Leu	missense	Exon 7 of 18	NP_001341738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.749C>T	p.Pro250Leu	missense	Exon 7 of 18	ENSP00000414914.2
	FGFR3	ENST00000481110.7	TSL:1	c.749C>T	p.Pro250Leu	missense	Exon 7 of 17	ENSP00000420533.2
	FGFR3	ENST00000352904.6	TSL:1	c.749C>T	p.Pro250Leu	missense	Exon 6 of 15	ENSP00000231803.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 238970 AF XY: 0.00

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: 0.0000478

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000619 AC: 9 AN: 1454808 Hom.: 0 Cov.: 39 AF XY: 0.00000692 AC XY: 5 AN XY: 722916

African (AFR) AF: 0.0000300 AC: 1 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85942

European-Finnish (FIN) AF: 0.0000194 AC: 1 AN: 51610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1108222

Other (OTH) AF: 0.00 AC: 0 AN: 60002

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Oct 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 250 of the FGFR3 protein (p.Pro250Leu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of FGFR3-related conditions (PMID: 12362036). ClinVar contains an entry for this variant (Variation ID: 533893). 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) indicates that this missense variant is expected to disrupt FGFR3 protein function with a positive predictive value of 80%. This variant disrupts the p.Pro250 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9042914, 10094188, 10861678, 15915095, 26740388). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Dec 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20824703, 30048571, 14577033, 12362036)

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGFR3: PM5, PS2:Moderate, PP3, PS4:Supporting

FGFR3-related disorder Uncertain:2

Feb 20, 2025

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.88 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with FGFR3-related disorder (PMID: 12362036). However, the evidence of pathogenicity is insufficient at this time. Different missense changes at the same codon (p.Pro250Arg, p.Pro250Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016340 /PMID: 31721094, 8841188 /3billion dataset). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Oct 08, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FGFR3 c.749C>T variant is predicted to result in the amino acid substitution p.Pro250Leu. This variant was reported in an individual with craniosynostosis and found to be inherited from her very mildly affected mother (Schindler et al 2002. PubMed ID: 12362036). This variant is reported in 0.0041% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-1803571-C-T). A different missense variant affecting the same amino acid is a common cause of isolated craniosynostosis (see for example, Kruszka. 2016. PubMed ID: 26740388 ). Although we suspect that this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.89	P
Vest4		0.69
MutPred		0.88		Loss of glycosylation at P250 (P = 0.0271)
MVP		0.97
MPC		0.63
ClinPred		0.99	D
GERP RS		3.1
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.90
gMVP		0.89
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs4647924; hg19: chr4-1803571;