rs146662137

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The ENST00000481110.7(FGFR3):​c.2191C>T​(p.Arg731Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,609,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

FGFR3
ENST00000481110.7 missense

Scores

2
2
12

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -6.32
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.029880911).
BP6
Variant 4-1806919-C-T is Benign according to our data. Variant chr4-1806919-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 585862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000107 (156/1457070) while in subpopulation AFR AF= 0.000629 (21/33404). AF 95% confidence interval is 0.000421. There are 0 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FGFR3NM_000142.5 linkuse as main transcriptc.2259C>T p.Thr753= synonymous_variant 17/18 ENST00000440486.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FGFR3ENST00000440486.8 linkuse as main transcriptc.2259C>T p.Thr753= synonymous_variant 17/185 NM_000142.5 P4P22607-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152104
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000717
AC:
17
AN:
237200
Hom.:
0
AF XY:
0.0000464
AC XY:
6
AN XY:
129382
show subpopulations
Gnomad AFR exome
AF:
0.000469
Gnomad AMR exome
AF:
0.0000889
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000662
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000107
AC:
156
AN:
1457070
Hom.:
0
Cov.:
36
AF XY:
0.0000952
AC XY:
69
AN XY:
724566
show subpopulations
Gnomad4 AFR exome
AF:
0.000629
Gnomad4 AMR exome
AF:
0.000113
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000701
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000106
Gnomad4 OTH exome
AF:
0.0000830
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74420
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000267
Hom.:
0
Bravo
AF:
0.000181
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000994
AC:
12
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJan 26, 2018- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 22, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
0.15
DANN
Benign
0.84
DEOGEN2
Benign
0.29
T
Eigen
Benign
-1.9
Eigen_PC
Benign
-2.1
FATHMM_MKL
Benign
0.042
N
LIST_S2
Benign
0.44
T
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.030
T
MetaSVM
Benign
-0.86
T
MutationTaster
Benign
1.0
D;D;D;D;D;N
PROVEAN
Benign
-1.7
N
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.0
B
Vest4
0.23
MVP
0.20
ClinPred
0.046
T
GERP RS
-9.3

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

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

Other links and lift over

dbSNP: rs146662137; hg19: chr4-1808646; COSMIC: COSV105834777; COSMIC: COSV105834777; API