4-1806604-G-A

Variant names:

• chr4-1806604-G-A
• rs121913480
• NM_000142.5:c.2089G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000142.5(FGFR3):​c.2089G>A​(p.Gly697Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.55
• Publications: 92 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 4-1806604-G-A is Pathogenic according to our data. Variant chr4-1806604-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2582278.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	NM_000142.5	MANE Select	c.2089G>A	p.Gly697Ser	missense	Exon 16 of 18	NP_000133.1
	FGFR3	NM_001163213.2		c.2095G>A	p.Gly699Ser	missense	Exon 16 of 18	NP_001156685.1
	FGFR3	NM_001354809.2		c.2092G>A	p.Gly698Ser	missense	Exon 16 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.2089G>A	p.Gly697Ser	missense	Exon 16 of 18	ENSP00000414914.2
	FGFR3	ENST00000481110.7	TSL:1	c.2021G>A	p.Arg674Gln	missense	Exon 15 of 17	ENSP00000420533.2
	FGFR3	ENST00000352904.6	TSL:1	c.1753G>A	p.Gly585Ser	missense	Exon 13 of 15	ENSP00000231803.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of urinary bladder Pathogenic:1

Laboratory of Urology, Hospital Clinic de Barcelona

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Benign	0.81
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.82
Sift	Benign	0.22	T
Sift4G	Benign	0.44	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.72		Gain of phosphorylation at G697 (P = 0.06)
MVP		0.95
MPC		2.2
ClinPred		0.88	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.72
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs121913480; hg19: chr4-1808331; COSMIC: COSV53400997;