rs778082287
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_033163.5(FGF8):āc.497A>Gā(p.Asn166Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
FGF8
NM_033163.5 missense
NM_033163.5 missense
Scores
3
7
4
Clinical Significance
Conservation
PhyloP100: 5.87
Genes affected
FGF8 (HGNC:3686): (fibroblast growth factor 8) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogensis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs revealed roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGF8 | NM_033163.5 | c.497A>G | p.Asn166Ser | missense_variant | 6/6 | ENST00000320185.7 | |
LOC105378457 | XR_007062268.1 | n.148T>C | non_coding_transcript_exon_variant | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGF8 | ENST00000320185.7 | c.497A>G | p.Asn166Ser | missense_variant | 6/6 | 1 | NM_033163.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250692Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135596
GnomAD3 exomes
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460870Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726784
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
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33
ExAC
?
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Holoprosencephaly sequence Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Muenke lab, National Institutes of Health | Apr 18, 2018 | Statistically different in zebrafish functional studies compared to the normal FGF8 isoform. However, experimental variability was detected between repeated independent studies. Experimental and bioinformatic predictions suggest a weak hypomorph. ACMG: PS3;PP3 (variable hypomorph; site affected by glycosylation based on this variant as well as synthetic codon variants tested for glycosylation changes reflected by altered electrophoretic mobility in Western blots). Stronger loss of activity seen with purely synthetic codon variants. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
1.0, 0.029, 0.15
.;D;B;B;B
Vest4
MutPred
0.68
.;Loss of stability (P = 0.099);.;.;.;
MVP
MPC
0.87
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at