NM_000142.5:c.2421A>G

Variant names:

• chr4-1807262-A-G
• rs121913103
• NM_000142.5:c.2421A>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.2421A>G​(p.Ter807Trpext*?) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 stop_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 3.42

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 4-1807262-A-G is Pathogenic according to our data. Variant chr4-1807262-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.2421A>G	p.Ter807Trpext*?	stop_lost	Exon 18 of 18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.2421A>G	p.Ter807Trpext*?	stop_lost	Exon 18 of 18	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 07, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This protein extension has been observed in individuals with thanatophoric dysplasia type I (PMID: 10425034, 25614871). For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the FGFR3 protein. Other variant(s) that result in a similarly extended protein product (p.*807Leuext*101) have been determined to be pathogenic (PMID: 10425034, 25728633; Invitae). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 65564). This variant is also known as p.X807Trp. This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the FGFR3 mRNA. It is expected to extend the length of the FGFR3 protein by 101 additional amino acid residues. -

Jun 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stop codon loss and change to a tryptophan codon, leading to protein extension and the addition of 101 amino acids at the C-terminus in a gene for which protein extension is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10425034, 25728633, 25614871, 19215249, 17509076, 17320202, 34358384) -

Thanatophoric dysplasia type 1 Pathogenic:2 Other:1

Apr 05, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This FGFR3 variant is absent from large population datasets and has been identified in individuals with thanatophoric dysplasia type I (TD I). c.2421A>G (p.Ter807Trp) results in the elimination of a termination codon and subsequent protein elongation. The 141 amino acid residues resulting from the elimination for the termination codon contain a highly hydrophobic domain that is rich in cysteine, which is consistent with the known molecular mechanism for TD type I. We consider this variant pathogenic. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 19, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Achondroplasia Pathogenic:1

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	0.44	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Polyphen		0.0040	B
Vest4		0.18
MutPred		0.51		Loss of methylation at K785 (P = 0.0069);
MVP		0.84
ClinPred		0.81	D
GERP RS		4.6

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: rs121913103; hg19: chr4-1808989; COSMIC: COSV53412428; COSMIC: COSV53412428;