4-1793830-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000142.5(FGFR3):​c.-102-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 199,314 control chromosomes in the GnomAD database, including 99,169 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 1.0 ( 73853 hom., cov: 33)
Exomes 𝑓: 1.0 ( 25316 hom. )

Consequence

FGFR3
NM_000142.5 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00005438
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.975
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 4-1793830-T-C is Benign according to our data. Variant chr4-1793830-T-C is described in ClinVar as [Benign]. Clinvar id is 379389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1793830-T-C is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FGFR3NM_000142.5 linkuse as main transcriptc.-102-3T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000440486.8 NP_000133.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FGFR3ENST00000440486.8 linkuse as main transcriptc.-102-3T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 5 NM_000142.5 ENSP00000414914 P4P22607-1

Frequencies

GnomAD3 genomes
AF:
0.997
AC:
148057
AN:
148516
Hom.:
73802
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.989
Gnomad AMI
AF:
1.00
Gnomad AMR
AF:
0.999
Gnomad ASJ
AF:
1.00
Gnomad EAS
AF:
1.00
Gnomad SAS
AF:
1.00
Gnomad FIN
AF:
1.00
Gnomad MID
AF:
0.997
Gnomad NFE
AF:
1.00
Gnomad OTH
AF:
0.999
GnomAD4 exome
AF:
0.999
AC:
50661
AN:
50692
Hom.:
25316
Cov.:
3
AF XY:
0.999
AC XY:
26536
AN XY:
26552
show subpopulations
Gnomad4 AFR exome
AF:
0.986
Gnomad4 AMR exome
AF:
1.00
Gnomad4 ASJ exome
AF:
1.00
Gnomad4 EAS exome
AF:
1.00
Gnomad4 SAS exome
AF:
1.00
Gnomad4 FIN exome
AF:
1.00
Gnomad4 NFE exome
AF:
1.00
Gnomad4 OTH exome
AF:
0.998
GnomAD4 genome
AF:
0.997
AC:
148161
AN:
148622
Hom.:
73853
Cov.:
33
AF XY:
0.997
AC XY:
72216
AN XY:
72434
show subpopulations
Gnomad4 AFR
AF:
0.989
Gnomad4 AMR
AF:
0.999
Gnomad4 ASJ
AF:
1.00
Gnomad4 EAS
AF:
1.00
Gnomad4 SAS
AF:
1.00
Gnomad4 FIN
AF:
1.00
Gnomad4 NFE
AF:
1.00
Gnomad4 OTH
AF:
0.999
Alfa
AF:
0.998
Hom.:
9792

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingAl Jalila Children’s Genomics Center, Al Jalila Childrens Speciality HospitalJun 25, 2020- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
12
DANN
Benign
0.45
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000054
dbscSNV1_RF
Benign
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs10023340; hg19: chr4-1795557; API