rs121913116

Variant names:

• chr4-1799395-C-T
• rs121913116
• NM_000142.5:c.251C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000142.5(FGFR3):​c.251C>T​(p.Ser84Leu) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S84S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.0340
• Publications: 7 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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82
• PP5: Variant 4-1799395-C-T is Pathogenic according to our data. Variant chr4-1799395-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16358.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.251C>T	p.Ser84Leu	missense	Exon 3 of 18	NP_000133.1	P22607-1
	FGFR3	NM_001163213.2		c.251C>T	p.Ser84Leu	missense	Exon 3 of 18	NP_001156685.1	P22607-2
	FGFR3	NM_001354809.2		c.251C>T	p.Ser84Leu	missense	Exon 3 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.251C>T	p.Ser84Leu	missense	Exon 3 of 18	ENSP00000414914.2	P22607-1
	FGFR3	ENST00000481110.7	TSL:1	c.251C>T	p.Ser84Leu	missense	Exon 3 of 17	ENSP00000420533.2	F8W9L4
	FGFR3	ENST00000352904.6	TSL:1	c.251C>T	p.Ser84Leu	missense	Exon 2 of 15	ENSP00000231803.1	P22607-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000812 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Achondroplasia (2)
2	-	-	not provided (2)
1	-	-	Achondroplasia;C0265269:Levy-Hollister syndrome;C0410529:Hypochondroplasia;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 (1)
1	-	-	Hypochondroplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.034
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.20
Sift	Uncertain	0.024	D
Sift4G	Benign	0.15	T
Polyphen		0.89	P
Vest4		0.28
MutPred		0.75		Loss of disorder (P = 0.0339)
MVP		0.67
MPC		0.25
ClinPred		0.81	D
GERP RS		2.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.14
gMVP		0.53
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121913116; hg19: chr4-1801122;