chr10-101770373-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_033163.5(FGF8):ā€‹c.691A>Gā€‹(p.Ser231Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,450,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

FGF8
NM_033163.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.49
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18361804).
BS2
High AC in GnomAdExome4 at 8 AD,Digenic gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGF8NM_033163.5 linkc.691A>G p.Ser231Gly missense_variant Exon 6 of 6 ENST00000320185.7 NP_149353.1 P55075-4A1A515

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGF8ENST00000320185.7 linkc.691A>G p.Ser231Gly missense_variant Exon 6 of 6 1 NM_033163.5 ENSP00000321797.2 P55075-4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000552
AC:
8
AN:
1450192
Hom.:
0
Cov.:
32
AF XY:
0.00000139
AC XY:
1
AN XY:
720470
show subpopulations
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:
0.00000722
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.691A>G (p.S231G) alteration is located in exon 6 (coding exon 6) of the FGF8 gene. This alteration results from a A to G substitution at nucleotide position 691, causing the serine (S) at amino acid position 231 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.041
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.63
.;D;.;.;.
Eigen
Benign
-0.073
Eigen_PC
Benign
-0.00089
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.85
D;D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.18
T;T;T;T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.2
.;L;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-1.3
.;N;N;N;N
REVEL
Benign
0.24
Sift
Uncertain
0.011
.;D;D;D;D
Sift4G
Benign
0.15
T;T;D;T;T
Polyphen
0.74, 0.82, 0.68
.;P;P;P;P
Vest4
0.14
MutPred
0.17
.;Loss of phosphorylation at S220 (P = 0.0388);.;.;.;
MVP
0.61
MPC
1.2
ClinPred
0.71
D
GERP RS
2.5
Varity_R
0.20
gMVP
0.40

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: rs1394398993; hg19: chr10-103530130; API