rs121913101

Positions:

• chr4-1807260-T-A
• chr4-1807260-T-C
• chr4-1807260-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000142.5(FGFR3):​c.2419T>A​(p.Ter807ArgextTer101) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 stop_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 2.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000142.5 Downstream stopcodon found after 897 codons.
• PP5: Variant 4-1807260-T-A is Pathogenic according to our data. Variant chr4-1807260-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 16335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.2419T>A	p.Ter807ArgextTer101	stop_lost	18/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.2419T>A	p.Ter807ArgextTer101	stop_lost	18/18	5	NM_000142.5	ENSP00000414914	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thanatophoric dysplasia type 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1995	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0265269:Levy-Hollister syndrome;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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 07, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2022

Published functional studies demonstrate this variant results in an extended protein which may have a damaging effect by causing a reduced level of glycosylated protein (Bonaventure et al., 2007; Gibbs et al., 2007); Variant resulting in loss of the termination codon leading to protein extension by 101 amino acids; Not observed at significant frequency in large population cohorts (gnomAD); Multiple other variants resulting in loss of termination codon and protein extension reported in association with thanatophoric dysplasia (HGMD); This variant is associated with the following publications: (PMID: 28254233, 17320202, 25614871, 20301540, 17509076, 25728633, 25800480, 34367232, 7647778) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	0.10	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Polyphen		0.13	B
Vest4		0.27
MutPred		0.65		Gain of solvent accessibility (P = 0.0078);
MVP		0.85
ClinPred		0.98	D
GERP RS		3.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913101; hg19: chr4-1808987;