NM_213647.3:c.586C>T
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_213647.3(FGFR4):c.586C>T(p.Arg196Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000756 in 1,587,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000070 ( 0 hom. )
Consequence
FGFR4
NM_213647.3 missense
NM_213647.3 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 4.69
Publications
0 publications found
Genes affected
FGFR4 (HGNC:3691): (fibroblast growth factor receptor 4) The protein encoded by this gene is a tyrosine kinase and cell surface receptor for fibroblast growth factors. The encoded protein is involved in the regulation of several pathways, including cell proliferation, cell differentiation, cell migration, lipid metabolism, bile acid biosynthesis, vitamin D metabolism, glucose uptake, and phosphate homeostasis. This protein consists 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 interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. [provided by RefSeq, Aug 2017]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152214
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000697 AC: 10AN: 1435684Hom.: 0 Cov.: 33 AF XY: 0.00000846 AC XY: 6AN XY: 709046 show subpopulations
GnomAD4 exome
AF:
AC:
10
AN:
1435684
Hom.:
Cov.:
33
AF XY:
AC XY:
6
AN XY:
709046
show subpopulations
African (AFR)
AF:
AC:
1
AN:
32928
American (AMR)
AF:
AC:
0
AN:
43364
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25660
East Asian (EAS)
AF:
AC:
3
AN:
38698
South Asian (SAS)
AF:
AC:
1
AN:
84760
European-Finnish (FIN)
AF:
AC:
0
AN:
52846
Middle Eastern (MID)
AF:
AC:
0
AN:
5684
European-Non Finnish (NFE)
AF:
AC:
5
AN:
1092604
Other (OTH)
AF:
AC:
0
AN:
59140
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.460
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74362 show subpopulations
GnomAD4 genome
AF:
AC:
2
AN:
152214
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
74362
show subpopulations
African (AFR)
AF:
AC:
2
AN:
41462
American (AMR)
AF:
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5194
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68040
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Sep 01, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.586C>T (p.R196C) alteration is located in exon 5 (coding exon 4) of the FGFR4 gene. This alteration results from a C to T substitution at nucleotide position 586, causing the arginine (R) at amino acid position 196 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;M;M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;.;.;D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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