4-1793937-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000142.5(FGFR3):​c.3G>A​(p.Met1?) variant causes a start 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

FGFR3
NM_000142.5 start_lost

Scores

5
4
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0830
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FGFR3NM_000142.5 linkuse as main transcriptc.3G>A p.Met1? start_lost 2/18 ENST00000440486.8 NP_000133.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FGFR3ENST00000440486.8 linkuse as main transcriptc.3G>A p.Met1? start_lost 2/185 NM_000142.5 ENSP00000414914 P4P22607-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1159450
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
561054
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 14, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with FGFR3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change affects the initiator methionine of the FGFR3 mRNA. The next in-frame methionine is located at codon 69. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.51
D;T;.;.;T;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.38
N
LIST_S2
Uncertain
0.90
D;D;D;D;D;.
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Benign
-0.59
T
MutationTaster
Benign
1.0
D;D;D;D;D;D
PROVEAN
Benign
-0.68
N;N;N;N;.;N
REVEL
Uncertain
0.42
Sift
Pathogenic
0.0
D;D;D;T;.;T
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
0.051
B;P;B;B;.;B
Vest4
0.85
MutPred
1.0
Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);Loss of glycosylation at P4 (P = 0.0682);
MVP
0.89
ClinPred
0.97
D
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.91
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-1795664; API