chr10-101770514-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2

The NM_033163.5(FGF8):​c.550C>T​(p.Arg184Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,334 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: not found (cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

FGF8
NM_033163.5 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84
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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.5674 (below the threshold of 3.09). Trascript score misZ: 1.0113 (below the threshold of 3.09). GenCC associations: The gene is linked to Kallmann syndrome, hypogonadotropic hypogonadism 6 with or without anosmia, hypogonadotropic hypogonadism, holoprosencephaly.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.944
BS2
High AC in GnomAdExome4 at 19 AD,Digenic gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGF8NM_033163.5 linkc.550C>T p.Arg184Cys 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.550C>T p.Arg184Cys missense_variant Exon 6 of 6 1 NM_033163.5 ENSP00000321797.2 P55075-4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.0000160
AC:
4
AN:
250682
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000469
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461334
Hom.:
0
Cov.:
32
AF XY:
0.0000151
AC XY:
11
AN XY:
727030
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33474
Gnomad4 AMR exome
AF:
0.0000224
AC:
1
AN:
44724
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26128
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39694
Gnomad4 SAS exome
AF:
0.0000464
AC:
4
AN:
86252
Gnomad4 FIN exome
AF:
0.0000189
AC:
1
AN:
52976
Gnomad4 NFE exome
AF:
0.0000117
AC:
13
AN:
1111938
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
60380
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

FGF8-related disorder Uncertain:1
Dec 22, 2022
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The FGF8 c.550C>T variant is predicted to result in the amino acid substitution p.Arg184Cys. This variant in the homozygous condition was reported in an individual with hypogonadotropic hypogonadism, idiopathic (Men et al 2019. PubMed ID: 31748124). This variant is reported in 0.0047% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-103530271-G-A). A different variant affecting the same amino acid (p.Arg184His) was reported to negatively affect the proliferation of human cardiomyocytes (Zhou. 2020. PubMed ID: 32664970). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
.;D;.;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Pathogenic
3.1
.;M;.;.;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.2
.;D;D;D;D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
.;D;D;D;D
Vest4
0.82
MVP
0.92
MPC
2.2
ClinPred
0.98
D
GERP RS
2.8
Varity_R
0.95
gMVP
0.82
Mutation Taster
=6/94
disease causing

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: rs369967262; hg19: chr10-103530271; COSMIC: COSV60142753; API