rs121913482

Variant names:

• chr4-1801837-C-T
• rs121913482
• NM_000142.5:c.742C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-1801837-C-T
• chr4-1801837-C-G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000142.5(FGFR3):​c.742C>T​(p.Arg248Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000282235: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R248R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:55 O:1
• Conservation: PhyloP100: 2.73
• Publications: 368 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P, Ambry Genetics, ClinGen
• Crouzon syndrome-acanthosis nigricans syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, Genomics England PanelApp, G2P
• hypochondroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P, Ambry Genetics
• lacrimoauriculodentodigital syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Muenke syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen, Genomics England PanelApp
• thanatophoric dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• thanatophoric dysplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Ambry Genetics, Genomics England PanelApp
• thanatophoric dysplasia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• camptodactyly-tall stature-scoliosis-hearing loss syndrome

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
• severe achondroplasia-developmental delay-acanthosis nigricans syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000282235: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product; SCV004239071: functional studies showing that it leads to ligand-independent FGFR3 dimerization.; SCV005438689: Experimental studies have shown that this missense change affects FGFR3 function Del Piccolo et. al., 2015.; SCV006583251: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25606676).; SCV004176920: Functional studies show that this variant leads to ligand-independent receptor activation, downstream activation of the mitogen-activated protein kinase pathway, increased cellular proliferation, and impaired apoptosis in multiple cell lines (Naski MC et al., PMID: 8640234; Hafner C et al., PMID: 20420824).; SCV000329627: Published functional studies indicate R248C alters FGFR3 dimer stabilization, activates FGFR3 by forming covalently bound dimers via disulfide bonds, and stimulates ERK phosphorylation (Del Piccolo et al., 2015; Foldynova-Trantirkova et al., 2012; Duperret et al., 2014); SCV000603712: Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization. Biophys J. 2015 Jan 20;108(2):272-8. Del Piccolo N et al.; SCV001389479: Experimental studies have shown that this missense change affects FGFR3 function (PMID: 1908846, 25606676).; SCV002107095: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 1908846; 25606676) - PS3_moderate."; SCV006059844: "functional studies have confirmed it results in FGFR3 activation (PMID: 19088846)."; SCV004100377: Recent functional studies have indicated the p.Arg248Cys variant promotes ligand-independent FGFR3 dimerization (Del Piccolo 2015), which is predicted to result in constitutive receptor activation, as is observed with other cysteine-substituted FGFR3 variants associated with TD type I (Adar 2002).; SCV005417711: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000142.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 4-1801837-C-T is Pathogenic according to our data. Variant chr4-1801837-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	NM_000142.5	MANE Select	c.742C>T	p.Arg248Cys	missense splice_region	Exon 7 of 18	NP_000133.1	P22607-1
	FGFR3	NM_001163213.2		c.742C>T	p.Arg248Cys	missense splice_region	Exon 7 of 18	NP_001156685.1	P22607-2
	FGFR3	NM_001354809.2		c.742C>T	p.Arg248Cys	missense splice_region	Exon 7 of 18	NP_001341738.1	X5D2G8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.742C>T	p.Arg248Cys	missense splice_region	Exon 7 of 18	ENSP00000414914.2	P22607-1
	FGFR3	ENST00000481110.7	TSL:1	c.742C>T	p.Arg248Cys	missense splice_region	Exon 7 of 17	ENSP00000420533.2	F8W9L4
	FGFR3	ENST00000352904.6	TSL:1	c.742C>T	p.Arg248Cys	missense splice_region	Exon 6 of 15	ENSP00000231803.1	P22607-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
16	-	-	Thanatophoric dysplasia type 1 (17)
13	-	-	not provided (13)
5	-	-	Achondroplasia (5)
2	-	-	Epidermal nevus (2)
2	-	-	FGFR3-related chondrodysplasia (2)
2	-	-	FGFR3-related disorder (2)
2	-	-	See cases (2)
1	-	-	Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0153594:Malignant tumor of testis;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0410529:Hypochondroplasia;C0699790:Carcinoma of colon;C1300257:Thanatophoric dysplasia, type 2;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer (1)
1	-	-	Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer;C5774286:Lacrimoauriculodentodigital syndrome 2 (1)
1	-	-	Cervical cancer (1)
1	-	-	Connective tissue disorder (1)
1	-	-	Hamartoma (1)
1	-	-	Malignant tumor of urinary bladder (1)
1	-	-	Muenke syndrome (1)
1	-	-	Multiple myeloma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		2.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.92		Loss of disorder (P = 0.028)
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		3.0
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.93
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs121913482; hg19: chr4-1803564; COSMIC: COSV53390662; COSMIC: COSV53390662;