10-101770490-AGCCCTTGCGGGGCCG-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4PP5

The NM_033163.5(FGF8):​c.559_573delCGGCCCCGCAAGGGC​(p.Arg187_Gly191del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGF8
NM_033163.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 5.81
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_033163.5.
PP5
Variant 10-101770490-AGCCCTTGCGGGGCCG-A is Pathogenic according to our data. Variant chr10-101770490-AGCCCTTGCGGGGCCG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 545457.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGF8NM_033163.5 linkc.559_573delCGGCCCCGCAAGGGC p.Arg187_Gly191del conservative_inframe_deletion 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.559_573delCGGCCCCGCAAGGGC p.Arg187_Gly191del conservative_inframe_deletion Exon 6 of 6 1 NM_033163.5 ENSP00000321797.2 P55075-4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461376
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
727030
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Jul 27, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in siblings with holoprosencephaly in published literature (Hong et al., 2016); Published Zebrafish model showed a complete loss of biological activity (Hong et al., 2016); In-frame deletion of 5 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26931467) -

Jun 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant, c.559_573del, results in the deletion of 5 amino acid(s) of the FGF8 protein (p.Arg187_Gly191del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of FGF8-related conditions (PMID: 26931467). This variant is also known as c.515-529delCCCGCAAGGGCCGGC. ClinVar contains an entry for this variant (Variation ID: 545457). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FGF8 function (PMID: 26931467). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Holoprosencephaly sequence Pathogenic:1
Apr 18, 2018
Muenke lab, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Family history of similarly affected female sibs with evidence of digenic inheritance of a paternal LOF allele in FGF8 and a maternal LOF allele in FGFR1. Established gene to gene interactions in animal models. This FGF8 variation is supported by experimental data and ACMG criteria: PS3;PM1/PM2/PM4;PP1. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs1554834321; hg19: chr10-103530247; API